Genetic Alterations on Chromosome 12 and Methods of Use Thereof for the Diagnosis and Treatment of Type 1 Diabetes

ABSTRACT

Compositions and methods for the detection and treatment of T1D are provided.

This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 60/894,649, filed on Mar. 13, 2007; U.S. Provisional Patent Application 60/910,019, filed Apr. 4, 2007; and U.S. Provisional Patent Application 60/940,274, filed May 25, 2007. The foregoing applications are incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to the fields of glucose metabolism, genetics and pathology associated with diabetes, particularly type I diabetes. More specifically, the invention provides a panel of genes containing single nucleotide polymorphisms which had heretofore not been associated with this disease. Methods and kits for using the sequences so identified for diagnostic and therapeutic treatment purposes are also provided, as are therapeutic compositions for management of diabetes.

BACKGROUND OF THE INVENTION

Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.

Type I diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells, a process believed to be strongly influenced by multiple genes and environmental factors. The incidence of T1D has been increasing in Western countries and has more than doubled in the United States over the past 30 years. The disease shows a strong familial component, with first-degree relatives of cases being at 15 times greater risk of T1D than a randomly selected member of the general population and monozygotic twins being concordant for T1D at a frequency of approximately 50%. However, while the genetic evidence is strong, the latter data suggests that an interplay with environmental factors also plays a key role in influencing T1D outcome.

The familial clustering of T1D is influenced by multiple genes. Variation in four loci has already been established to account for a significant proportion of the familial aggregation of T1D. These include the major histocompatibility complex (MHC) region on 6p21 (including the HLA-DRB1, -DQA1 and -DRQ1 genes¹); the insulin/insulin-like growth factor 2 gene complex (INS-IGF2) on 11p15²⁻⁴, the protein tyrosine phosphatase-22 (PTPN22) gene on 1p13^(5, 6) and the gene encoding cytotoxic T-lymphocyte-associated protein 4 (CTLA4) on 2q31^(7, 8). The interleukin-2 receptor alpha (CD25) locus on 10p15⁹ has also been implicated in the pathogenesis of T1D but remains to be replicated by independent studies. In addition, spontaneous mouse model studies of T1D have implicated numerous other regions that have been confirmed in replication studies¹⁰. Several other loci have also been implicated in human association studies with T1D but the effects of these implicated genes remain controversial and are subject to confirmation in independent studies utilizing sufficient sample sizes. Together, these studies suggest that many more T1D susceptibility genes remain to be discovered. It is also clear that there are differences in genetic susceptibility to T1D between populations. An explanation for this variation may be related to differing frequencies of T1D causative and protective variants between different populations and ethnic groups, a hypothesis that needs to be addressed in multi-center, multi-national studies that are truly trans-continental.

SUMMARY OF THE INVENTION

In accordance with the present invention, T1D-associated SNPs have been identified which are indicative of an increased or reduced risk of developing T1D. Thus, in one aspect, nucleic acids comprising at least one genetic alteration identified in Tables 1-3 are provided. Such nucleic acids and the proteins encoded thereby have utility in the diagnosis and management of type 1 diabetes (T1D).

In another aspect of the invention, methods for assessing susceptibility for developing T1D are provided. An exemplary method entails providing a target nucleic acid from a patient sample, said target nucleic acid having a predetermined sequence in the normal population, and assessing said target nucleic acid for the presence of a single nucleotide polymorphism which is indicative of an increased or decreased risk of developing T1D. Such genetic alterations include, without limitation, inversion, deletion, duplication, and insertion of at least one nucleotide in said sequence.

Preferably, the genetic alteration is a single nucleotide polymorphism at the 12q13 region of chromosome 12, said SNP being associated with increased risk of developing T1D. Preferably, the SNP is present on locus 18 and comprises an allele selected from the group consisting of G of rs10876864, C of rs1701704 and G of rs773107. These aforementioned SNPs are present on a region of chromosome 12q13 harboring the RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3 genes.

The methods of the invention also include the detection of any of the T1D associated genetic alterations comprising the single nucleotide polymorphisms set forth in Tables 1-3 for the diagnosis of T1D. Kits and microarrays for practicing the foregoing methods are also provided.

In yet another embodiment, a method of managing T1D is provided which entails administering a therapeutic agent to a patient in need thereof. The therapeutic agent can be a small molecule, an antibody, a protein, an oligonucleotide, or a siRNA molecule.

In another aspect of the invention, a method for identifying agents that bind and/or modulate RPS26 functional activity is provided, as well as pharmaceutical compositions comprising said agent in a biologically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Pairwise linkage disequilibrium diagram of the locus on 12q13. This ‘gold plot’ is derived from HapMap CEU data corresponding to a region spanning from 54567159 (rs12298127) to 54806642 (rs17118317) base pairs on chromosome 12 (Build 35); intensity of shading is proportional to D′. The relative genomic location of the genes is shown.

FIG. 2. RPS26 sequence located on chromosome 12q13. Both the nucleic acid sequence (SEQ ID NO: 1) in panel A and protein sequence (SEQ ID NO: 2) in panel B of RPS26 corresponding to GenBank Accession number NM_(—)001029 are shown. This sequence is the basis of the candidate siRNA molecules in Table 9, SEQ ID NOs: 1913-2002.

FIG. 3. CDK2 nucleic acid sequences used to design candidate siRNA molecules. Panel A shows GenBank Accession number NM_(—)052827 (SEQ ID NO: 3) which corresponds to Table 5, SEQ ID NOs: 12-251, and panel B shows GenBank Accession number NM_(—)001798 (SEQ ID NO: 4) corresponding to SEQ ID NOs: 252-488 of Table 5.

FIG. 4. ERBB3 nucleic acid sequence used to design candidate siRNA molecules. Panel A shows GenBank Accession number NM_(—)001005915 (SEQ ID NO: 5) which corresponds with SEQ ID NOs: 489-568 of Table 6, and panel B shows GenBank Accession number NM_(—)001982 (SEQ ID NO: 6) which corresponds with SEQ ID NOs: 569-1120 of Table 6.

FIG. 5. IKZF4 nucleic acid sequence used to design candidate siRNA molecules. The figure shows GenBank Accession number NM_(—)022465 (SEQ ID NO: 7) which corresponds with SEQ ID NOs: 1121-1592 of Table 7.

FIG. 6. RAB5B nucleic acid sequence used to design candidate siRNA molecules. The figure shows GenBank Accession number NM_(—)002868 (SEQ ID NO: 8) which corresponds with SEQ ID NO: 1593-1912 of Table 8.

FIG. 7 SUOX nucleic acid sequences used to design candidate siRNA molecules. Panel A shows GenBank Accession number NM_(—)000456 (SEQ ID NO: 9) which corresponds with SEQ ID NOs: 2003-2204 of Table 10, panel B shows GenBank Accession number NM_(—)001032386 (SEQ ID NO: 10) which corresponds with SEQ ID NOs: 2205-2394 of Table 10, and panel C shows GenBank Accession number NM_(—)001032387 (SEQ ID NO: 11) which corresponds with SEQ ID NOs: 2395-2576 of Table 10.

DETAILED DESCRIPTION OF THE INVENTION

A number of genetic determinants of T1D have already been established through candidate gene studies, primarily with the major histocompatibility complex (MHC) but also with other loci. To identify novel genetic factors that confer risk of T1D, a genome-wide association (GWA) study in a large pediatric study cohort of Western European decent was performed. In addition to confirming previously identified loci, we also observed and replicated association to the 12q13 region of chromosome 12, with increased risk of developing T1D. Three common non-coding variants (G of rs10876864, C of rs1701704 and G of rs773107) in strong LD conferred risk for T1D. These SNPs are present on a region of chromosome 12q13 harboring the RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3 genes.

These results provide evidence for a novel genetic factor that contributes substantially to the pathogenesis of T1D, including a common variant conferring risk for developing disease, and thus providing a promising new T1D therapeutic and diagnostic target.

The following definitions are provided to facilitate an understanding of the present invention:

For purposes of the present invention, “a” or “an” entity refers to one or more of that entity; for example, “a cDNA” refers to one or more cDNA or at least one cDNA. As such, the terms “a” or “an,” “one or more” and “at least one” can be used interchangeably herein. It is also noted that the terms “comprising,” “including,” and “having” can be used interchangeably. Furthermore, a compound “selected from the group consisting of” refers to one or more of the compounds in the list that follows, including mixtures (i.e. combinations) of two or more of the compounds. According to the present invention, an isolated, or biologically pure molecule is a compound that has been removed from its natural milieu. As such, “isolated” and “biologically pure” do not necessarily reflect the extent to which the compound has been purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthetic techniques or can be produced by any such chemical synthetic route.

A “single nucleotide polymorphism (SNP)” refers to a change in which a single base in the DNA differs from the usual base at that position. These single base changes are called SNPs or “snips.” Millions of SNP's have been cataloged in the human genome. Some SNPs such that which causes sickle cell are responsible for disease. Other SNPs are normal variations in the genome.

The term “genetic alteration” as used herein refers to a change from the wild-type or reference sequence of one or more nucleic acid molecules. Genetic alterations include without limitation, base pair substitutions, additions and deletions of at least one nucleotide from a nucleic acid molecule of known sequence.

The phrase “Type 1 diabetes (T1D)” refers to a chronic (lifelong) disease that occurs when the pancreas produces too little insulin to regulate blood sugar levels appropriately. T1D, often called juvenile or insulin-dependent diabetes results from altered metabolism of carbohydrates (including sugars such as glucose), proteins, and fats. In type 1 diabetes, the beta cells of the pancreas produce little or no insulin, the hormone that allows glucose to enter body cells. Once glucose enters a cell, it is used as fuel. Without adequate insulin, glucose builds up in the bloodstream instead of going into the cells. The body is unable to use this glucose for energy despite high levels in the bloodstream, leading to increased hunger. In addition, the high levels of glucose in the blood cause the patient to urinate more, which in turn causes excessive thirst. Within 5 to 10 years after diagnosis, the insulin-producing beta cells of the pancreas are completely destroyed, and no more insulin is produced.

“T1D-associated SNP or specific marker” is a SNP or marker which is associated with an increased or decreased risk of developing T1D not found normal patients who do not have this disease. Such markers may include but are not limited to nucleic acids, proteins encoded thereby, or other small molecules. Type 1 diabetes can occur at any age, but it usually starts in people younger than 30. Symptoms are usually severe and occur rapidly. The exact cause of type 1 diabetes is not known. Type 1 diabetes accounts for 3% of all new cases of diabetes each year. There is 1 new case per every 7,000 children per year. New cases are less common among adults older than 20.

The term “solid matrix” as used herein refers to any format, such as beads, microparticles, a microarray, the surface of a microtitration well or a test tube, a dipstick or a filter. The material of the matrix may be polystyrene, cellulose, latex, nitrocellulose, nylon, polyacrylamide, dextran or agarose. “Sample” or “patient sample” or “biological sample” generally refers to a sample which may be tested for a particular molecule, preferably an T1D specific marker molecule, such as a marker shown in the tables provided below. Samples may include but are not limited to cells, body fluids, including blood, serum, plasma, urine, saliva, tears, pleural fluid and the like.

The phrase “consisting essentially of” when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the functional and novel characteristics of the sequence.

“Target nucleic acid” as used herein refers to a previously defined region of a nucleic acid present in a complex nucleic acid mixture wherein the defined wild-type region contains at least one known nucleotide variation which may or may not be associated with T1D. The nucleic acid molecule may be isolated from a natural source by cDNA cloning or subtractive hybridization or synthesized manually. The nucleic acid molecule may be synthesized manually by the triester synthetic method or by using an automated DNA synthesizer.

With regard to nucleic acids used in the invention, the term “isolated nucleic acid” is sometimes employed. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous (in the 5′ and 3′ directions) in the naturally occurring genome of the organism from which it was derived. For example, the “isolated nucleic acid” may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryote or eukaryote. An “isolated nucleic acid molecule” may also comprise a cDNA molecule. An isolated nucleic acid molecule inserted into a vector is also sometimes referred to herein as a recombinant nucleic acid molecule.

With respect to RNA molecules, the term “isolated nucleic acid” primarily refers to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from RNA molecules with which it would be associated in its natural state (i.e., in cells or tissues), such that it exists in a “substantially pure” form. By the use of the term “enriched” in reference to nucleic acid it is meant that the specific DNA or RNA sequence constitutes a significantly higher fraction (2-5 fold) of the total DNA or RNA present in the cells or solution of interest than in normal cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other DNA or RNA present, or by a preferential increase in the amount of the specific DNA or RNA sequence, or by a combination of the two. However, it should be noted that “enriched” does not imply that there are no other DNA or RNA sequences present, just that the relative amount of the sequence of interest has been significantly increased.

It is also advantageous for some purposes that a nucleotide sequence be in purified form. The term “purified” in reference to nucleic acid does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment (compared to the natural level, this level should be at least 2-5 fold greater, e.g., in terms of mg/ml). Individual clones isolated from a cDNA library may be purified to electrophoretic homogeneity. The claimed DNA molecules obtained from these clones can be obtained directly from total DNA or from total RNA. The cDNA clones are not naturally occurring, but rather are preferably obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The construction of a cDNA library from mRNA involves the creation of a synthetic substance (cDNA) and pure individual cDNA clones can be isolated from the synthetic library by clonal selection of the cells carrying the cDNA library. Thus, the process which includes the construction of a cDNA library from mRNA and isolation of distinct cDNA clones yields an approximately 10⁻⁶-fold purification of the native message. Thus, purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. Thus, the term “substantially pure” refers to a preparation comprising at least 50-60% by weight the compound of interest (e.g., nucleic acid, oligonucleotide, etc.). More preferably, the preparation comprises at least 75% by weight, and most preferably 90-99% by weight, the compound of interest. Purity is measured by methods appropriate for the compound of interest.

The term “complementary” describes two nucleotides that can form multiple favorable interactions with one another. For example, adenine is complementary to thymine as they can form two hydrogen bonds. Similarly, guanine and cytosine are complementary since they can form three hydrogen bonds. Thus if a nucleic acid sequence contains the following sequence of bases, thymine, adenine, guanine and cytosine, a “complement” of this nucleic acid molecule would be a molecule containing adenine in the place of thymine, thymine in the place of adenine, cytosine in the place of guanine, and guanine in the place of cytosine. Because the complement can contain a nucleic acid sequence that forms optimal interactions with the parent nucleic acid molecule, such a complement can bind with high affinity to its parent molecule.

With respect to single stranded nucleic acids, particularly oligonucleotides, the term “specifically hybridizing” refers to the association between two single-stranded nucleotide molecules of sufficiently complementary sequence to permit such hybridization under pre-determined conditions generally used in the art (sometimes termed “substantially complementary”). In particular, the term refers to hybridization of an oligonucleotide with a substantially complementary sequence contained within a single-stranded DNA or RNA molecule of the invention, to the substantial exclusion of hybridization of the oligonucleotide with single-stranded nucleic acids of non-complementary sequence. For example, specific hybridization can refer to a sequence which hybridizes to any T1D specific marker gene or nucleic acid, but does not hybridize to other human nucleotides. Also polynucleotide which “specifically hybridizes” may hybridize only to a T1D specific marker, such a T1D-specific marker shown in Tables 1-3. Appropriate conditions enabling specific hybridization of single stranded nucleic acid molecules of varying complementarity are well known in the art. For instance, one common formula for calculating the stringency conditions required to achieve hybridization between nucleic acid molecules of a specified sequence homology is set forth below (Sambrook et al., Molecular Cloning, Cold Spring Harbor Laboratory (1989):

T _(m)=81.5° C.+16.6 Log [Na+]+0.41(% G+C)−0.63(% formamide)−600/#bp in duplex

As an illustration of the above formula, using [Na+]=[0.368] and 50% formamide, with GC content of 42% and an average probe size of 200 bases, the T_(m) is 57° C. The T_(m) of a DNA duplex decreases by 1-1.5° C. with every 1% decrease in homology. Thus, targets with greater than about 75% sequence identity would be observed using a hybridization temperature of 42° C.

The stringency of the hybridization and wash depend primarily on the salt concentration and temperature of the solutions. In general, to maximize the rate of annealing of the probe with its target, the hybridization is usually carried out at salt and temperature conditions that are 20-25° C. below the calculated T_(m) of the hybrid. Wash conditions should be as stringent as possible for the degree of identity of the probe for the target. In general, wash conditions are selected to be approximately 12-20° C. below the T_(m) of the hybrid. In regards to the nucleic acids of the current invention, a moderate stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 2×SSC and 0.5% SDS at 55° C. for 15 minutes. A high stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 1×SSC and 0.5% SDS at 65° C. for 15 minutes. A very high stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 0.1×SSC and 0.5% SDS at 65° C. for 15 minutes.

The term “oligonucleotide” or “oligo” as used herein means a short sequence of DNA or DNA derivatives typically 8 to 35 nucleotides in length, primers, or probes. An oligonucleotide can be derived synthetically, by cloning or by amplification. An oligo is defined as a nucleic acid molecule comprised of two or more ribo- or deoxyribonucleotides, preferably more than three. The exact size of the oligonucleotide will depend on various factors and on the particular application and use of the oligonucleotide. The term “derivative” is intended to include any of the above described variants when comprising an additional chemical moiety not normally a part of these molecules. These chemical moieties can have varying purposes including, improving solubility, absorption, biological half life, decreasing toxicity and eliminating or decreasing undesirable side effects.

The term “probe” as used herein refers to an oligonucleotide, polynucleotide or nucleic acid, either RNA or DNA, whether occurring naturally as in a purified restriction enzyme digest or produced synthetically, which is capable of annealing with or specifically hybridizing to a nucleic acid with sequences complementary to the probe. A probe may be either single-stranded or double-stranded. The exact length of the probe will depend upon many factors, including temperature, source of probe and use of the method. For example, for diagnostic applications, depending on the complexity of the target sequence, the oligonucleotide probe typically contains 15-25 or more nucleotides, although it may contain fewer nucleotides. The probes herein are selected to be complementary to different strands of a particular target nucleic acid sequence. This means that the probes must be sufficiently complementary so as to be able to “specifically hybridize” or anneal with their respective target strands under a set of pre-determined conditions. Therefore, the probe sequence need not reflect the exact complementary sequence of the target. For example, a non-complementary nucleotide fragment may be attached to the 5′ or 3′ end of the probe, with the remainder of the probe sequence being complementary to the target strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the probe, provided that the probe sequence has sufficient complementarity with the sequence of the target nucleic acid to anneal therewith specifically.

The term “primer” as used herein refers to an oligonucleotide, either RNA or DNA, either single-stranded or double-stranded, either derived from a biological system, generated by restriction enzyme digestion, or produced synthetically which, when placed in the proper environment, is able to functionally act as an initiator of template-dependent nucleic acid synthesis. When presented with an appropriate nucleic acid template, suitable nucleoside triphosphate precursors of nucleic acids, a polymerase enzyme, suitable cofactors and conditions such as a suitable temperature and pH, the primer may be extended at its 3′ terminus by the addition of nucleotides by the action of a polymerase or similar activity to yield a primer extension product. The primer may vary in length depending on the particular conditions and requirement of the application. For example, in diagnostic applications, the oligonucleotide primer is typically 15-25 or more nucleotides in length. The primer must be of sufficient complementarity to the desired template to prime the synthesis of the desired extension product, that is, to be able anneal with the desired template strand in a manner sufficient to provide the 3′ hydroxyl moiety of the primer in appropriate juxtaposition for use in the initiation of synthesis by a polymerase or similar enzyme. It is not required that the primer sequence represent an exact complement of the desired template. For example, a non-complementary nucleotide sequence may be attached to the 5′ end of an otherwise complementary primer. Alternatively, non-complementary bases may be interspersed within the oligonucleotide primer sequence, provided that the primer sequence has sufficient complementarity with the sequence of the desired template strand to functionally provide a template-primer complex for the synthesis of the extension product.

Polymerase chain reaction (PCR) has been described in U.S. Pat. Nos. 4,683,195, 4,800,195, and 4,965,188, the entire disclosures of which are incorporated by reference herein.

An “siRNA” refers to a molecule involved in the RNA interference process for a sequence-specific post-transcriptional gene silencing or gene knockdown by providing small interfering RNAs (siRNAs) that has homology with the sequence of the targeted gene. Small interfering RNAs (siRNAs) can be synthesized in vitro or generated by ribonuclease III cleavage from longer dsRNA and are the mediators of sequence-specific mRNA degradation. Preferably, the siRNA of the invention are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. The siRNA can be synthesized as two separate, complementary RNA molecules, or as a single RNA molecule with two complementary regions. Commercial suppliers of synthetic RNA molecules or synthesis reagents include Applied Biosystems (Foster City, Calif., USA), Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, Colo., USA), Pierce Chemical (part of Perbio Science, Rockford, Ill., USA), Glen Research (Sterling, Va., USA), ChemGenes (Ashland, Mass., USA) and Cruachem (Glasgow, UK). Specific siRNA constructs for inhibiting the mRNA of one of the six genes on 12q13, or SNP-containing genes may be between 15-35 nucleotides in length, and more typically about 21 nucleotides in length. Specific siRNA constructs for inhibiting RPS26 mRNA may be between 15-35 nucleotides in length, and more typically about 21 nucleotides in length. A list of candidate siRNAs directed to CDK2 ERBB3, IKZF4, RAB5B, RPS26, and SUOX are provided in Tables 5-10 respectively.

The term “vector” relates to a single or double stranded circular nucleic acid molecule that can be infected, transfected or transformed into cells and replicate independently or within the host cell genome. A circular double stranded nucleic acid molecule can be cut and thereby linearized upon treatment with restriction enzymes. An assortment of vectors, restriction enzymes, and the knowledge of the nucleotide sequences that are targeted by restriction enzymes are readily available to those skilled in the art, and include any replicon, such as a plasmid, cosmid, bacmid, phage or virus, to which another genetic sequence or element (either DNA or RNA) may be attached so as to bring about the replication of the attached sequence or element. A nucleic acid molecule of the invention can be inserted into a vector by cutting the vector with restriction enzymes and ligating the two pieces together.

Many techniques are available to those skilled in the art to facilitate transformation, transfection, or transduction of the expression construct into a prokaryotic or eukaryotic organism. The terms “transformation”, “transfection”, and “transduction” refer to methods of inserting a nucleic acid and/or expression construct into a cell or host organism. These methods involve a variety of techniques, such as treating the cells with high concentrations of salt, an electric field, or detergent, to render the host cell outer membrane or wall permeable to nucleic acid molecules of interest, microinjection, peptide-tethering, PEG-fusion, and the like.

The term “promoter element” describes a nucleotide sequence that is incorporated into a vector that, once inside an appropriate cell, can facilitate transcription factor and/or polymerase binding and subsequent transcription of portions of the vector DNA into mRNA. In one embodiment, the promoter element of the present invention precedes the 5′ end of the T1D specific marker nucleic acid molecule such that the latter is transcribed into mRNA. Host cell machinery then translates mRNA into a polypeptide.

Those skilled in the art will recognize that a nucleic acid vector can contain nucleic acid elements other than the promoter element and the T1D specific marker gene nucleic acid molecule. These other nucleic acid elements include, but are not limited to, origins of replication, ribosomal binding sites, nucleic acid sequences encoding drug resistance enzymes or amino acid metabolic enzymes, and nucleic acid sequences encoding secretion signals, localization signals, or signals useful for polypeptide purification.

A “replicon” is any genetic element, for example, a plasmid, cosmid, bacmid, plastid, phage or virus that is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded.

An “expression operon” refers to a nucleic acid segment that may possess transcriptional and translational control sequences, such as promoters, enhancers, translational start signals (e.g., ATG or AUG codons), polyadenylation signals, terminators, and the like, and which facilitate the expression of a polypeptide coding sequence in a host cell or organism.

As used herein, the terms “reporter,” “reporter system”, “reporter gene,” or “reporter gene product” shall mean an operative genetic system in which a nucleic acid comprises a gene that encodes a product that when expressed produces a reporter signal that is a readily measurable, e.g., by biological assay, immunoassay, radio immunoassay, or by colorimetric, fluorogenic, chemiluminescent or other methods. The nucleic acid may be either RNA or DNA, linear or circular, single or double stranded, antisense or sense polarity, and is operatively linked to the necessary control elements for the expression of the reporter gene product. The required control elements will vary according to the nature of the reporter system and whether the reporter gene is in the form of DNA or RNA, but may include, but not be limited to, such elements as promoters, enhancers, translational control sequences, poly A addition signals, transcriptional termination signals and the like.

The introduced nucleic acid may or may not be integrated (covalently linked) into nucleic acid of the recipient cell or organism. In bacterial, yeast, plant and mammalian cells, for example, the introduced nucleic acid may be maintained as an episomal element or independent replicon such as a plasmid. Alternatively, the introduced nucleic acid may become integrated into the nucleic acid of the recipient cell or organism and be stably maintained in that cell or organism and further passed on or inherited to progeny cells or organisms of the recipient cell or organism. Finally, the introduced nucleic acid may exist in the recipient cell or host organism only transiently.

The term “selectable marker gene” refers to a gene that when expressed confers a selectable phenotype, such as antibiotic resistance, on a transformed cell.

The term “operably linked” means that the regulatory sequences necessary for expression of the coding sequence are placed in the DNA molecule in the appropriate positions relative to the coding sequence so as to effect expression of the coding sequence. This same definition is sometimes applied to the arrangement of transcription units and other transcription control elements (e.g. enhancers) in an expression vector.

The terms “recombinant organism,” or “transgenic organism” refer to organisms which have a new combination of genes or nucleic acid molecules. A new combination of genes or nucleic acid molecules can be introduced into an organism using a wide array of nucleic acid manipulation techniques available to those skilled in the art. The term “organism” relates to any living being comprised of a least one cell. An organism can be as simple as one eukaryotic cell or as complex as a mammal. Therefore, the phrase “a recombinant organism” encompasses a recombinant cell, as well as eukaryotic and prokaryotic organism.

The term “isolated protein” or “isolated and purified protein” is sometimes used herein. This term refers primarily to a protein produced by expression of an isolated nucleic acid molecule of the invention. Alternatively, this term may refer to a protein that has been sufficiently separated from other proteins with which it would naturally be associated, so as to exist in “substantially pure” form. “Isolated” is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification, addition of stabilizers, or compounding into, for example, immunogenic preparations or pharmaceutically acceptable preparations.

A “specific binding pair” comprises a specific binding member (sbm) and a binding partner (bp) which have a particular specificity for each other and which in normal conditions bind to each other in preference to other molecules. Examples of specific binding pairs are antigens and antibodies, ligands and receptors and complementary nucleotide sequences. The skilled person is aware of many other examples. Further, the term “specific binding pair” is also applicable where either or both of the specific binding member and the binding partner comprise a part of a large molecule. In embodiments in which the specific binding pair comprises nucleic acid sequences, they will be of a length to hybridize to each other under conditions of the assay, preferably greater than 10 nucleotides long, more preferably greater than 15 or 20 nucleotides long. “Sample” or “patient sample” or “biological sample” generally refers to a sample which may be tested for a particular molecule, preferably a T1D specific marker molecule, such as a marker shown in Tables 1-3. Samples may include but are not limited to cells, body fluids, including blood, serum, plasma, urine, saliva, tears, pleural fluid and the like.

The terms “agent” and “test compound” are used interchangeably herein and denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, small molecules, antibodies, peptides, peptide/DNA complexes, and any nucleic acid based molecule, for example an oligo, which exhibits the capacity to modulate the activity of the SNP containing nucleic acids described herein or their encoded proteins. Agents are evaluated for potential biological activity by inclusion in screening assays described herein below.

The term “modulate” as used herein refers increasing or decreasing. For example, the term modulate refers to the ability of a compound or test agent to interfere with signaling or activity of a gene or protein of the present invention. Therefore, modulating the signaling mediated by RPS26 means that an agent or compound inhibits or enhances the activity of the proteins encoded by the gene. This includes altering the activity of natural killer cells, and preventing autoimmune beta cell destruction.

Methods of Using T1D-Associated SNPS for T1D Detection Assays

T1D SNP containing nucleic acids, including but not limited to those listed in Tables 1-3, may be used for a variety of purposes in accordance with the present invention. T1D-associated SNP containing DNA, RNA, or fragments thereof may be used as probes to detect the presence of and/or expression of T1D specific markers. Methods in which T1D specific marker nucleic acids may be utilized as probes for such assays include, but are not limited to: (1) in situ hybridization; (2) Southern hybridization (3) northern hybridization; and (4) assorted amplification reactions such as polymerase chain reactions (PCR).

Further, assays for detecting T1D-associated SNPs may be conducted on any type of biological sample, including but not limited to body fluids (including blood, urine, serum, gastric lavage), any type of cell (such as white blood cells, mononuclear cells) or body tissue.

From the foregoing discussion, it can be seen that T1D associated SNP containing nucleic acids, vectors expressing the same, T1D SNP containing marker proteins and anti-T1D specific marker antibodies of the invention can be used to detect T1D associated SNPs in body tissue, cells, or fluid, and alter T1D SNP containing marker protein expression for purposes of assessing the genetic and protein interactions involved in T1D.

In most embodiments for screening for T1D-associated SNPs, the T1D-associated SNP containing nucleic acid in the sample will initially be amplified, e.g. using PCR, to increase the amount of the template as compared to other sequences present in the sample. This allows the target sequences to be detected with a high degree of sensitivity if they are present in the sample. This initial step may be avoided by using highly sensitive array techniques that are becoming increasingly important in the art.

Alternatively, new detection technologies can overcome this limitation and enable analysis of small samples containing as little as 1 μg of total RNA. Using Resonance Light Scattering (RLS) technology, as opposed to traditional fluorescence techniques, multiple reads can detect low quantities of mRNAs using biotin labeled hybridized targets and anti-biotin antibodies. Another alternative to PCR amplification involves planar wave guide technology (PWG) to increase signal-to-noise ratios and reduce background interference. Both techniques are commercially available from Qiagen Inc. (USA).

Thus, any of the aforementioned techniques may be used to detect or quantify T1D-associated SNP marker expression and accordingly, detect patient susceptibility for developing T1D.

Kits and Articles of Manufacture

Any of the aforementioned products can be incorporated into a kit which may contain an T1D-associated SNP specific marker polynucleotide or one or more such markers immobilized on a Gene Chip, an oligonucleotide, a polypeptide, a peptide, an antibody, a label, marker, or reporter, a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a vessel for administration, an assay substrate, or any combination thereof.

Methods of Using T1D-Associated SNPS for Development of Therapeutic Agents

Since the SNPs identified herein have been associated with the etiology of T1D, methods for identifying agents that modulate the activity of the genes and their encoded products containing such SNPs should result in the generation of efficacious therapeutic agents for the treatment of a variety of disorders associated with this condition.

Chromosome 12 contains regions which provide suitable targets for the rational design of therapeutic agents which modulate their activity. Small peptide molecules corresponding to these regions may be used to advantage in the design of therapeutic agents which effectively modulate the activity of the encoded proteins.

Molecular modeling should facilitate the identification of specific organic molecules with capacity to bind to the active site of the proteins encoded by the SNP containing nucleic acids based on conformation or key amino acid residues required for function. A combinatorial chemistry approach will be used to identify molecules with greatest activity and then iterations of these molecules will be developed for further cycles of screening.

The polypeptides or fragments employed in drug screening assays may either be free in solution, affixed to a solid support or within a cell. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant polynucleotides expressing the polypeptide or fragment, preferably in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may determine, for example, formation of complexes between the polypeptide or fragment and the agent being tested, or examine the degree to which the formation of a complex between the polypeptide or fragment and a known substrate is interfered with by the agent being tested.

Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity for the encoded polypeptides and is described in detail in Geysen, PCT published application WO 84/03564, published on Sep. 13, 1984. Briefly stated, large numbers of different, small peptide test compounds, such as those described above, are synthesized on a solid substrate, such as plastic pins or some other surface. The peptide test compounds are reacted with the target polypeptide and washed. Bound polypeptide is then detected by methods well known in the art.

A further technique for drug screening involves the use of host eukaryotic cell lines or cells (such as described above) which have a nonfunctional or altered T1D associated gene. These host cell lines or cells are defective at the polypeptide level. The host cell lines or cells are grown in the presence of drug compound. The rate of cellular metabolism of the host cells is measured to determine if the compound is capable of regulating cellular metabolism in the defective cells. Host cells contemplated for use in the present invention include but are not limited to bacterial cells, fungal cells, insect cells, mammalian cells, and plant cells. The T1D-associated SNP encoding DNA molecules may be introduced singly into such host cells or in combination to assess the phenotype of cells conferred by such expression. Methods for introducing DNA molecules are also well known to those of ordinary skill in the art. Such methods are set forth in Ausubel et al. eds., Current Protocols in Molecular Biology, John Wiley & Sons, NY, N.Y. 1995, the disclosure of which is incorporated by reference herein.

Cells and cell lines suitable for studying the effects of the SNP encoding nucleic acids on glucose metabolism and methods of use thereof for drug discovery are provided. Such cells and cell lines will be transfected with the SNP encoding nucleic acids described herein and the effects on glucagon secretion, insulin secretion and/or beta cell apoptosis can be determined. Such cells and cell lines will also be contacted with the siRNA molecules provided herein to assess the effects thereof on glucagon secretion, insulin secretion and/or beta cell apoptosis. The siRNA molecules will be tested alone and in combination of 2, 3, 4, and 5 siRNAs to identify the most efficacious combination for down regulating the gene targets comprising the SNPs described herein (e.g., RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3). Cells suitable for these purposes include, without limitation, INS cells (ATCC CRL 11605), PC12 cells (ATCC CRL 1721), MIN6 cells, alpha-TC6 cells and INS-1 832/13 cells (Fernandez et al., J. of Proteome Res. (2007). 7:400-411). Pancreatic islet cells can be isolated and cultured as described in Joseph, J. et al., (J. Biol. Chem. (2004) 279:51049). Diao et al. (J. Biol. Chem. (2005) 280:33487-33496), provide methodology for assessing the effects of the SNP encoding nucleic acids and/or the siRNAs provided herein on glucagon secretion and insulin secretion. Park, J. et al. (J. of Bioch. and Mol. Biol. (2007) 40:1058-68) provide methodology for assessing the effect of these nucleic acid molecules on glucosamine induced beta cell apoptosis in pancreatic islet cells.

A wide variety of expression vectors are available that can be modified to express the novel DNA or RNA sequences of this invention. The specific vectors exemplified herein are merely illustrative, and are not intended to limit the scope of the invention. Expression methods are described by Sambrook et al. Molecular Cloning: A Laboratory Manual or Current Protocols in Molecular Biology 16.3-17.44 (1989). Expression methods in Saccharomyces are also described in Current Protocols in Molecular Biology (1989).

Suitable vectors for use in practicing the invention include prokaryotic vectors such as the pNH vectors (Stratagene Inc., 11099 N. Torrey Pines Rd., La Jolla, Calif. 92037), pET vectors (Novogen Inc., 565 Science Dr., Madison, Wis. 53711) and the pGEX vectors (Pharmacia LKB Biotechnology Inc., Piscataway, N.J. 08854). Examples of eukaryotic vectors useful in practicing the present invention include the vectors pRc/CMV, pRc/RSV, and pREP (Invitrogen, 11588 Sorrento Valley Rd., San Diego, Calif. 92121); pcDNA3.1/V5&H is (Invitrogen); baculovirus vectors such as pVL1392, pVL1393, or pAC360 (Invitrogen); and yeast vectors such as YRP17, YIPS, and YEP24 (New England Biolabs, Beverly, Mass.), as well as pRS403 and pRS413 Stratagene Inc.); Picchia vectors such as pHIL-D1 (Phillips Petroleum Co., Bartlesville, Okla. 74004); retroviral vectors such as PLNCX and pLPCX (Clontech); and adenoviral and adeno-associated viral vectors.

Promoters for use in expression vectors of this invention include promoters that are operable in prokaryotic or eukaryotic cells. Promoters that are operable in prokaryotic cells include lactose (lac) control elements, bacteriophage lambda (pL) control elements, arabinose control elements, tryptophan (trp) control elements, bacteriophage T7 control elements, and hybrids thereof. Promoters that are operable in eukaryotic cells include Epstein Barr virus promoters, adenovirus promoters, SV40 promoters, Rous Sarcoma Virus promoters, cytomegalovirus (CMV) promoters, baculovirus promoters such as AcMNPV polyhedrin promoter, Picchia promoters such as the alcohol oxidase promoter, and Saccharomyces promoters such as the gal4 inducible promoter and the PGK constitutive promoter, as well as neuronal-specific platelet-derived growth factor promoter (PDGF), the Thy-1 promoter, the hamster and mouse Prion promoter (MoPrP), and the Glial fibrillar acidic protein (GFAP) for the expression of transgenes in glial cells.

In addition, a vector of this invention may contain any one of a number of various markers facilitating the selection of a transformed host cell. Such markers include genes associated with temperature sensitivity, drug resistance, or enzymes associated with phenotypic characteristics of the host organisms.

Host cells expressing the T1D-associated SNPs of the present invention or functional fragments thereof provide a system in which to screen potential compounds or agents for the ability to modulate the development of T1D. Thus, in one embodiment, the nucleic acid molecules of the invention may be used to create recombinant cell lines for use in assays to identify agents which modulate aspects of lectin binding. Also provided herein are methods to screen for compounds capable of modulating the function of proteins encoded by the SNP containing nucleic acids described below.

Another approach entails the use of phage display libraries engineered to express fragment of the polypeptides encoded by the SNP containing nucleic acids on the phage surface. Such libraries are then contacted with a combinatorial chemical library under conditions wherein binding affinity between the expressed peptide and the components of the chemical library may be detected. U.S. Pat. Nos. 6,057,098 and 5,965,456 provide methods and apparatus for performing such assays.

The goal of rational drug design is to produce structural analogs of biologically active polypeptides of interest or of small molecules with which they interact (e.g., agonists, antagonists, inhibitors) in order to fashion drugs which are, for example, more active or stable forms of the polypeptide, or which, e.g., enhance or interfere with the function of a polypeptide in vivo. See, e.g., Hodgson, (1991) Bio/Technology 9:19-21. In one approach, discussed above, the three-dimensional structure of a protein of interest or, for example, of the protein-substrate complex, is solved by x-ray crystallography, by nuclear magnetic resonance, by computer modeling or most typically, by a combination of approaches. Less often, useful information regarding the structure of a polypeptide may be gained by modeling based on the structure of homologous proteins. An example of rational drug design is the development of HIV protease inhibitors (Erickson et al., (1990) Science 249:527-533). In addition, peptides may be analyzed by an alanine scan (Wells, (1991) Meth. Enzym. 202:390-411). In this technique, an amino acid residue is replaced by Ala, and its effect on the peptide's activity is determined. Each of the amino acid residues of the peptide is analyzed in this manner to determine the important regions of the peptide.

It is also possible to isolate a target-specific antibody, selected by a functional assay, and then to solve its crystal structure. In principle, this approach yields a pharmacophore upon which subsequent drug design can be based.

One can bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original molecule. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced banks of peptides. Selected peptides would then act as the pharmacophore.

Thus, one may design drugs which have, e.g., improved polypeptide activity or stability or which act as inhibitors, agonists, antagonists, etc. of polypeptide activity. By virtue of the availability of SNP containing nucleic acid sequences described herein, sufficient amounts of the encoded polypeptide may be made available to perform such analytical studies as x-ray crystallography. In addition, the knowledge of the protein sequence provided herein will guide those employing computer modeling techniques in place of, or in addition to x-ray crystallography.

In another embodiment, the availability of T1D-associated SNP containing nucleic acids enables the production of strains of laboratory mice carrying the T1D-associated SNPs of the invention. Transgenic mice expressing the T1D-associated SNP of the invention provide a model system in which to examine the role of the protein encoded by the SNP containing nucleic acid in the development and progression towards T1D. Methods of introducing transgenes in laboratory mice are known to those of skill in the art. Three common methods include: (1) integration of retroviral vectors encoding the foreign gene of interest into an early embryo; (2) injection of DNA into the pronucleus of a newly fertilized egg; and (3) the incorporation of genetically manipulated embryonic stem cells into an early embryo. Production of the transgenic mice described above will facilitate the molecular elucidation of the role that a target protein plays in various cellular metabolic processes, including: aberrant lipid deposition, altered cellular metabolism and glucose regulation. Such mice provide an in vivo screening tool to study putative therapeutic drugs in a whole animal model and are encompassed by the present invention.

The term “animal” is used herein to include all vertebrate animals, except humans. It also includes an individual animal in all stages of development, including embryonic and fetal stages. A “transgenic animal” is any animal containing one or more cells bearing genetic information altered or received, directly or indirectly, by deliberate genetic manipulation at the subcellular level, such as by targeted recombination or microinjection or infection with recombinant virus. The term “transgenic animal” is not meant to encompass classical cross-breeding or in vitro fertilization, but rather is meant to encompass animals in which one or more cells are altered by or receive a recombinant DNA molecule. This molecule may be specifically targeted to a defined genetic locus, be randomly integrated within a chromosome, or it may be extrachromosomally replicating DNA. The term “germ cell line transgenic animal” refers to a transgenic animal in which the genetic alteration or genetic information was introduced into a germ line cell, thereby conferring the ability to transfer the genetic information to offspring. If such offspring, in fact, possess some or all of that alteration or genetic information, then they, too, are transgenic animals.

The alteration of genetic information may be foreign to the species of animal to which the recipient belongs, or foreign only to the particular individual recipient, or may be genetic information already possessed by the recipient. In the last case, the altered or introduced gene may be expressed differently than the native gene. Such altered or foreign genetic information would encompass the introduction of T1D-associated SNP containing nucleotide sequences.

The DNA used for altering a target gene may be obtained by a wide variety of techniques that include, but are not limited to, isolation from genomic sources, preparation of cDNAs from isolated mRNA templates, direct synthesis, or a combination thereof.

A preferred type of target cell for transgene introduction is the embryonal stem cell (ES). ES cells may be obtained from pre-implantation embryos cultured in vitro (Evans et al., (1981) Nature 292:154-156; Bradley et al., (1984) Nature 309:255-258; Gossler et al., (1986) Proc. Natl. Acad. Sci. 83:9065-9069). Transgenes can be efficiently introduced into the ES cells by standard techniques such as DNA transfection or by retrovirus-mediated transduction. The resultant transformed ES cells can thereafter be combined with blastocysts from a non-human animal. The introduced ES cells thereafter colonize the embryo and contribute to the germ line of the resulting chimeric animal.

One approach to the problem of determining the contributions of individual genes and their expression products is to use isolated T1D-associated SNP genes as insertional cassettes to selectively inactivate a wild-type gene in totipotent ES cells (such as those described above) and then generate transgenic mice. The use of gene-targeted ES cells in the generation of gene-targeted transgenic mice was described, and is reviewed elsewhere (Frohman et al., (1989) Cell 56:145-147; Bradley et al., (1992) Bio/Technology 10:534-539).

Techniques are available to inactivate or alter any genetic region to a mutation desired by using targeted homologous recombination to insert specific changes into chromosomal alleles. However, in comparison with homologous extrachromosomal recombination, which occurs at a frequency approaching 100%, homologous plasmid-chromosome recombination was originally reported to only be detected at frequencies between 10⁻⁶ and 10⁻³. Nonhomologous plasmid-chromosome interactions are more frequent occurring at levels 10⁵-fold to 10² fold greater than comparable homologous insertion.

To overcome this low proportion of targeted recombination in murine ES cells, various strategies have been developed to detect or select rare homologous recombinants. One approach for detecting homologous alteration events uses the polymerase chain reaction (PCR) to screen pools of transformant cells for homologous insertion, followed by screening of individual clones. Alternatively, a positive genetic selection approach has been developed in which a marker gene is constructed which will only be active if homologous insertion occurs, allowing these recombinants to be selected directly. One of the most powerful approaches developed for selecting homologous recombinants is the positive-negative selection (PNS) method developed for genes for which no direct selection of the alteration exists. The PNS method is more efficient for targeting genes which are not expressed at high levels because the marker gene has its own promoter. Non-homologous recombinants are selected against by using the Herpes Simplex virus thymidine kinase (HSV-TK) gene and selecting against its nonhomologous insertion with effective herpes drugs such as gancyclovir (GANC) or (1-(2-deoxy-2-fluoro-B-D arabinofluranosyl)-5-iodou-racil, (FIAU). By this counter selection, the number of homologous recombinants in the surviving transformants can be increased. Utilizing T1D-associated SNP containing nucleic acid as a targeted insertional cassette provides means to detect a successful insertion as visualized, for example, by acquisition of immunoreactivity to an antibody immunologically specific for the polypeptide encoded by T1D-associated SNP nucleic acid and, therefore, facilitates screening/selection of ES cells with the desired genotype.

As used herein, a knock-in animal is one in which the endogenous murine gene, for example, has been replaced with human T1D-associated SNP containing gene of the invention. Such knock-in animals provide an ideal model system for studying the development of T1D.

As used herein, the expression of a T1D-associated SNP containing nucleic acid, fragment thereof, or a T1D-associated SNP fusion protein can be targeted in a “tissue specific manner” or “cell type specific manner” using a vector in which nucleic acid sequences encoding all or a portion of T1D-associated SNP are operably linked to regulatory sequences (e.g., promoters and/or enhancers) that direct expression of the encoded protein in a particular tissue or cell type. Such regulatory elements may be used to advantage for both in vitro and in vivo applications. Promoters for directing tissue specific expression of proteins are well known in the art and described herein.

The nucleic acid sequence encoding the T1D-associated SNP of the invention may be operably linked to a variety of different promoter sequences for expression in transgenic animals. Such promoters include, but are not limited to a prion gene promoter such as hamster and mouse Prion promoter (MoPrP), described in U.S. Pat. No. 5,877,399 and in Borchelt et al., Genet. Anal. 13(6) (1996) pages 159-163; a rat neuronal specific enolase promoter, described in U.S. Pat. Nos. 5,612,486, and 5,387,742; a platelet-derived growth factor B gene promoter, described in U.S. Pat. No. 5,811,633; a brain specific dystrophin promoter, described in U.S. Pat. No. 5,849,999; a Thy-1 promoter; a PGK promoter; a CMV promoter; a neuronal-specific platelet-derived growth factor B gene promoter; and Glial fibrillar acidic protein (GFAP) promoter for the expression of transgenes in glial cells.

Methods of use for the transgenic mice of the invention are also provided herein. Transgenic mice into which a nucleic acid containing the T1D-associated SNP or its encoded protein have been introduced are useful, for example, to develop screening methods to screen therapeutic agents to identify those capable of modulating the development of T1D.

Pharmaceuticals and Peptide Therapies

The elucidation of the role played by the T1D associated SNPs described herein in cellular metabolism facilitates the development of pharmaceutical compositions useful for treatment and diagnosis of T1D. These compositions may comprise, in addition to one of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.

Whether it is a polypeptide, antibody, peptide, nucleic acid molecule, small molecule or other pharmaceutically useful compound according to the present invention that is to be given to an individual, administration is preferably in a “prophylactically effective amount” or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual.

As it is presently understood, RNA interference involves a multi-step process. Double stranded RNAs are cleaved by the endonuclease Dicer to generate nucleotide fragments (siRNA). The siRNA duplex is resolved into 2 single stranded RNAs, one strand being incorporated into a protein-containing complex where it functions as guide RNA to direct cleavage of the target RNA (Schwarz et al, Mol. Cell. 10:537 548 (2002), Zamore et al, Cell 101:25 33 (2000)), thus silencing a specific genetic message (see also Zeng et al, Proc. Natl. Acad. Sci. 100:9779 (2003)).

The invention includes a method of treating T1D in a mammal. Preferably, the mammal is a human, and the term “patient” as used herein refers to a human. An exemplary method entails administering to the mammal a pharmaceutically effective amount of siRNA directed to SNP sequences in a patient. The following discussion focuses on RPS26, but should be construed to also include siRNA directed to CDK2, ERBB3, IKZF4, RAB5B, and SUOX, all of which are considered for siRNA inhibition using the constructs in Tables 5-10. The siRNA inhibits the expression of wild type or variant-SNP-containing RPS26 sequences.

Specific siRNA preparations directed at inhibiting the expression of RPS26 or variant SNP-containing RPS26, as well as delivery methods are provided as a novel therapy to treat T1D. SiRNA oligonucleotides directed to RPS26 sequences specifically hybridize with nucleic acids encoding RPS26 and interfere with RPS26 gene expression. The siRNA can be delivered to a patient in vivo either systemically or locally with carriers, as discussed below. The compositions of the invention may be used alone or in combination with other agents or genes encoding proteins to augment the efficacy of the compositions.

A “membrane permeant peptide sequence” refers to a peptide sequence which is able to facilitate penetration and entry of the RPS26 inhibitor across the cell membrane. Exemplary peptides include with out limitation, the signal sequence from Karposi fibroblast growth factor exemplified herein, the HIV tat peptide (Vives et al., J. Biol. Chem., 272:16010-16017, 1997), Nontoxic membrane translocation peptide from protamine (Park et al., FASEB J. 19(11):1555-7, 2005), CHARIOTS delivery reagent (Active Motif; U.S. Pat. No. 6,841,535) and the antimicrobial peptide Buforin 2.

In one embodiment of the invention siRNAs are delivered for therapeutic benefit. There are several ways to administer the siRNA of the invention to in vivo to treat T1D including, but not limited to, naked siRNA delivery, siRNA conjugation and delivery, liposome carrier-mediated delivery, polymer carrier delivery, nanoparticle compositions, plasmid-based methods, and the use of viruses.

siRNA composition of the invention can comprise a delivery vehicle, including liposomes, for administration to a subject, carriers and diluents and their salts, and/or can be present in pharmaceutically acceptable formulations. This can be necessary to allow the siRNA to cross the cell membrane and escape degradation. Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; and Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelman et al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT WO 94/02595 further describe the general methods for delivery of nucleic acid molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule.

The frequency of administration of the siRNA to a patient will also vary depending on several factors including, but not limited to, the type and severity of the T1D to be treated, the route of administration, the age and overall health of the individual, the nature of the siRNA, and the like. It is contemplated that the frequency of administration of the siRNA to the patient may vary from about once every few months to about once a month, to about once a week, to about once per day, to about several times daily.

Pharmaceutical compositions that are useful in the methods of the invention may be administered systemically in parenteral, oral solid and liquid formulations, ophthalmic, suppository, aerosol, topical or other similar formulations. In addition to the appropriate siRNA, these pharmaceutical compositions may contain pharmaceutically-acceptable carriers and other ingredients known to enhance and facilitate drug administration. Thus such compositions may optionally contain other components, such as adjuvants, e.g., aqueous suspensions of aluminum and magnesium hydroxides, and/or other pharmaceutically acceptable carriers, such as saline. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer the appropriate siRNA to a patient according to the methods of the invention. The use of nanoparticles to deliver siRNAs, as well as cell membrane permeable peptide carriers that can be used are described in Crombez et al., Biochemical Society Transactions v35:p44 (2007).

Methods of the invention directed to treating T1D involve the administration of RPS26 siRNA in a pharmaceutical composition. RPS26 siRNA is administered to an individual as a pharmaceutical composition comprising RPS26 siRNA and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include aqueous solutions such as physiologically buffered saline, other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.

A pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize the RPS26 siRNA or increase the absorption of the agent. Such physiologically acceptable compounds include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. One skilled in the art would know that the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable compound, depends, for example, on the route of administration of the RPS26 siRNA.

One skilled in the art appreciates that a pharmaceutical composition comprising RPS26 siRNA can be administered to a subject by various routes including, for example, orally or parenterally, such as intravenously (i.v.), intramuscularly, subcutaneously, intraorbitally, intranasally, intracapsularly, intraperitoneally (i.p.), intracisternally, intra-tracheally (i.t.), or intra-articularly or by passive or facilitated absorption. The same routes of administration can be used other pharmaceutically useful compounds, for example, small molecules, nucleic acid molecules, peptides, antibodies and polypeptides as discussed herein.

A pharmaceutical composition comprising RPS26 siRNA inhibitor also can be incorporated, if desired, into liposomes, microspheres, microbubbles, or other polymer matrices (Gregoriadis, Liposome Technology, Vols. I to III, 2nd ed., CRC Press, Boca Raton Fla. (1993)). Liposomes, for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

The pharmaceutical preparation comprises a siRNA targeting RPS26 or an expression vector encoding for an siRNA targeting RPS26 or SNP-containing RPS26. Such pharmaceutical preparations can be administered to a patient for treating T1D.

Expression vectors for the expression of siRNA molecules preferably employ a strong promoter which may be constitutive or regulated. Such promoters are well known in the art and include, but are not limited to, RNA polymerase II promoters, the T7 RNA polymerase promoter, and the RNA polymerase III promoters U6 and H1 (see, e.g., Myslinski et al. (2001) Nucl. Acids Res., 29:2502 09).

A formulated siRNA composition can be a composition comprising one or more siRNA molecules or a vector encoding one or more siRNA molecules independently or in combination with a cationic lipid, a neutral lipid, and/or a polyethyleneglycol-diacylglycerol (PEG-DAG) or PEG-cholesterol (PEG-Chol) conjugate. Non-limiting examples of expression vectors are described in Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002, Nature Biotechnology, 19, 500-505.

A lipid nanoparticle composition is a composition comprising one or more biologically active molecules independently or in combination with a cationic lipid, a neutral lipid, and/or a polyethyleneglycol-diacylglycerol (i.e., polyethyleneglycol diacylglycerol (PEG-DAG), PEG-cholesterol, or PEG-DMB) conjugate. In one embodiment, the biologically active molecule is encapsulated in the lipid nanoparticle as a result of the process of providing and aqueous solution comprising a biologically active molecule of the invention (i.e., siRNA), providing an organic solution comprising lipid nanoparticle, mixing the two solutions, incubating the solutions, dilution, ultrafiltration, resulting in concentrations suitable to produce nanoparticle compositions.

Nucleic acid molecules can be administered to cells by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins. (see for example Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722)

Cationic lipids and polymers are two classes of non-viral siRNA delivery which can form complexes with negatively charged siRNA. The self-assembly PEG-ylated polycation polyethylenimine (PEI) has also been used to condense and protect siRNAs (Schiffelers et al., 2004, Nuc. Acids Res. 32: 141-110). The siRNA complex can be condensed into a nanoparticle to allow efficient uptake of the siRNA through endocytosis. Also, the nucleic acid-condensing property of protamine has been combined with specific antibodies to deliver siRNAs and can be used in the invention (Song et al., 2005, Nat. Biotech. 23:709-717).

In order to treat an individual having T1D, to alleviate a sign or symptom of the disease, RPS26 siRNA should be administered in an effective dose, and can be sirected to SNP containing RPS26 sequences. The total treatment dose can be administered to a subject as a single dose or can be administered using a fractionated treatment protocol, in which multiple doses are administered over a more prolonged period of time, for example, over the period of a day to allow administration of a daily dosage or over a longer period of time to administer a dose over a desired period of time. One skilled in the art would know that the amount of RPS26 siRNA required to obtain an effective dose in a subject depends on many factors, including the age, weight and general health of the subject, as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose so as to obtain an effective dose for treating an individual having T1D.

The effective dose of RPS26 siRNA will depend on the mode of administration, and the weight of the individual being treated. The dosages described herein are generally those for an average adult but can be adjusted for the treatment of children. The dose will generally range from about 0.001 mg to about 1000 mg.

The concentration of RPS26 siRNA in a particular formulation will depend on the mode and frequency of administration. A given daily dosage can be administered in a single dose or in multiple doses so long as the RPS26 siRNA concentration in the formulation results in the desired daily dosage. One skilled in the art can adjust the amount of RPS26 siRNA in the formulation to allow administration of a single dose or in multiple doses that provide the desired concentration of RPS26 siRNA over a given period of time.

In an individual suffering from T1D, in particular a more severe form of the disease, administration of RPS26 siRNA can be particularly useful when administered in combination, for example, with a conventional agent for treating such a disease. The skilled artisan would administer RPS26 siRNA, alone or in combination and would monitor the effectiveness of such treatment using routine methods such as pulmonary function determination, radiologic, immunologic or, where indicated, histopathologic methods. Other conventional agents for the treatment of diabetes include insulin administration, glucagon administration or agents that alter levels of either of these two molecules. Glucophage®, Avandia®, Actos®, Januvia® and Glucovance® are examples of such agents.

Administration of the pharmaceutical preparation is preferably in an “effective amount” this being sufficient to show benefit to the individual. This amount prevents, alleviates, abates, or otherwise reduces the severity of T1D symptoms in a patient.

The pharmaceutical preparation is formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment. Each dosage should contain a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier. Procedures for determining the appropriate dosage unit are well known to those skilled in the art.

Dosage units may be proportionately increased or decreased based on the weight of the patient. Appropriate concentrations for alleviation of a particular pathological condition may be determined by dosage concentration curve calculations, as known in the art.

As mentioned previously, a preferred embodiment of the invention comprises delivery of the SNP-containing RPS26 siRNA to a patient in need thereof, and candidate siRNA compositions for use in the invention are provided in Tables 5-10 (e.g., candidate siRNAs in Table 5=CDK2, Table 6=ERBB3, Table 7=IKZF4, Table 8=RAB5B, Table 9=RPS26, Table 10=SUOX). The sequences suitable for use include several siRNA duplexes (i.e., sense and antisense sequences for a gene target region), as well as several sequences of ‘sense’ strand alone. Those of skill in the art can determine the sequence of an antisense siRNA strand based on the disclosure of the sense strand, and will appreciate the difference between “U” and “T” designations in the sequences which correspond to RNA and DNA molecules, respectively.

The following examples are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention in any way.

Example I

550,000 single nucleotide polymorphisms (SNPs) were genotyped with the Illumina Human Hap550 Genotyping BeadChip¹¹ on the study population of 563 T1D probands of European ancestry and 1,146 controls without T1D and with matching ancestry (based on self report) plus 483 complete T1D family trios of the same ancestry. Following this process, 16 trios, 2 cases and 3 controls were removed due to genotyping yields <90%. All patients had clinically proven T1D.

In the case-control analysis, single-marker allele frequencies were compared using χ² statistics for all markers while the transmission disequilibrium test (TDT) was used to calculate P-values of transmission distortion from heterozygous parents in affected parent-child trios. The resulting P-values from the case-control and family-based analyses were then combined using Fisher's method¹² to quantify the overall evidence for association.

Association signals were further assessed to identify signals that fulfilled the following criteria: (1) More than one SNP at a given locus exhibiting the same level of association in combined results from the Stage 1 case-control (after EIGENSTRAT adjustment for population stratification) and TDT analyses, with P<1×10⁻⁴; (2) the separate results from the Stage 1 case-control association and TDT analyses had to be P<0.05 each for more than one SNP at a given locus; (3) Odds ratios (OR) had to be in the same direction (more than one SNP at a given locus) in both the TDT and combined results.

Overall, 62 SNPs at a total of 24 loci satisfying the above criteria were selected (see Table 1). Following a replication attempt in the Stage 2 cohort, three SNPs at locus 18 resulted in significant association (see Table 2), namely allele G of rs10876864, allele C of rs1701704 and allele G of rs773107. These three SNPs reside on chromosome 12q13 in the vicinity of the following genes i.e. in a block of linkage disequilibrium: RAS-associated protein (RAB5B), in which rs773107 resides; Cyclin-dependent kinase 2 isoform 1 (CDK2); Sulfite oxidase (SUOX); Zinc finger protein subfamily 1A4 (IKZF4); Ribosomal protein S26 (RPS26); ErbB-3 isoform s precursor (ERBB3). As such, replicated association of T1D to a region on chromosome 12q13 harboring the genes RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3 has been observed.

Standard convention for presenting the risk conferred by a given SNP is to describe the risk numerically for the less frequent allele in the population i.e. the minor allele. On occasions, the minor allele is less frequent in the cases than in the controls and therefore yields a risk of less than 1 (i.e. it is termed “protective”). In this event, it is the major, or more common, allele that confers risk. SNPs that show association are not necessarily causative themselves, rather they tag the mutation which must reside on a nearby region (i.e. within a few kilobases). The causative mutation itself may confer higher risk and be rarer. Thus, the SNP association essentially indicates that there is a causative mutation nearby and that this SNP-containing gene is involved in the pathogenesis of the disease and therefore can be utilized to detect susceptibility thereto. Many surrogate SNPs can be employed to capture the same signal, and here they have been categorized into three parts: CATEGORY 1: r2>0.9; CATEGORY 2: r2=0.8-0.9; CATEGORY 3: r2<0.8-0.7; see Table 3. Surrogates for these three SNPs have also been identified and are provided in Table 3 below.

Down regulation of RPS26 mRNA expression levels (or any of the genes marked by the SNPs described herein, i.e., RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3) is desirable to inhibit production of the chromosome 12 gene product. Reduction in the expression level of this protein should impede or prevent the development of T1D. siRNA can be employed to regulate this locus, irrespective of the genetic status of the individual. Accordingly, candidate siRNA molecules to be delivered to patients are listed in Tables 5-10. The genetic status is useful to predict who will develop the disease so it can be determined who will particularly benefit from therapeutic intervention. Yet those individuals who do not have this specific genetic predisposition of T1D, but have a family history of the disease or have another type of genetic predisposition, could also benefit.

TABLE 1 Stage 1 candidate SNPs: Locus Chr No SNP Allele Case control P TDT OR TDT P Combined P Aff freq Ctrl frq OR 1 1 rs7543568 C 0.036 0.51 3.50 × 10⁻⁴ 2.00 × 10⁻⁴ 0.070 0.088 0.77 1 1 rs12094260 G 0.0058 0.49 0.0017 1.00 × 10⁻⁴ 0.049 0.067 0.72 1 2 rs2841578 A 1.50 × 10⁻³ 1.32 0.027 5.00 × 10⁻⁴ 0.159 0.132 1.25 1 2 rs1452619 G 1.53 × 10⁻³ 1.34 0.022 4.00 × 10⁻⁴ 0.160 0.132 1.25 2 3 rs6717144 T 9.82 × 10⁻⁴ 0.81 0.043 5.00 × 10⁻⁴ 0.274 0.305 0.86 2 3 rs7605368 A 2.66 × 10⁻³ 0.70 2.26 × 10⁻³ 7.84 × 10⁻⁵ 0.194 0.226 0.83 2 3 rs12617390 G 1.86 × 10⁻³ 0.71 4.90 × 10⁻³ 1.00 × 10⁻⁴ 0.198 0.231 0.82 2 4 rs1348904 G 0.0043 1.29 9.38 × 10⁻³ 4.00 × 10⁻⁴ 0.373 0.331 1.21 2 4 rs12467601 C 0.0050 1.27 0.013 7.00 × 10⁻⁴ 0.374 0.333 1.20 3 5 rs2168422 A 6.99 × 10⁻³ 1.30 0.013 9.00 × 10⁻⁴ 0.293 0.252 1.24 3 5 rs7621973 C 1.70 × 10⁻² 1.36 4.67 × 10⁻³ 8.00 × 10⁻⁴ 0.270 0.235 1.20 3 5 rs9310978 A 0.00362 1.26 0.025 9.00 × 10⁻⁴ 0.308 0.277 1.16 3 6 rs694429 G 0.0017 1.34 0.015 3.00 × 10⁻⁴ 0.255 0.210 1.29 3 6 rs792829 G 4.94 × 10⁻² 1.38 1.60 × 10⁻³ 8.00 × 10⁻⁴ 0.369 0.336 1.15 3 7 rs333335 C 1.76 × 10⁻³ 1.27 0.011 2.00 × 10⁻⁴ 0.458 0.411 1.21 3 7 rs333318 T 6.35 × 10⁻³ 0.79 0.014 9.00 × 10⁻⁴ 0.415 0.447 0.88 4 8 rs6856274 G 2.78 × 10⁻⁵ 1.26 0.040 1.62 × 10⁻⁵ 0.244 0.203 1.27 4 8 rs1486993 A 2.26 × 10⁻⁵ 1.25 0.046 1.52 × 10⁻⁵ 0.244 0.203 1.27 4 8 rs1486973 T 1.85 × 10⁻⁴ 1.28 0.029 6.94 × 10⁻⁵ 0.227 0.190 1.25 4 8 rs4388143 A 1.28 × 10⁻³ 0.78 9.13 × 10⁻³ 1.00 × 10⁻⁴ 0.431 0.474 0.84 6 9 rs214506 C 0.019 1.43 2.14 × 10⁻⁴ 5.34 × 10⁻⁵ 0.481 0.443 1.17 6 9 rs214566 G 0.0015 1.33 0.037 6.00 × 10⁻⁴ 0.173 0.131 1.39 6 9 rs214532 A 0.0029 1.32 0.013 4.00 × 10⁻⁴ 0.274 0.231 1.25 6 9 rs445149 G 0.0060 1.33 0.012 8.00 × 10⁻⁴ 0.265 0.226 1.24 6 9 rs725550 G 0.0078 0.66 8.50 × 10⁻⁴ 8.56 × 10⁻⁵ 0.178 0.218 0.78 6 10 rs1471540 T 0.0011 1.32 0.025 3.00 × 10⁻⁴ 0.196 0.146 1.43 6 10 rs597544 T 0.0017 1.33 0.046 8.00 × 10⁻⁴ 0.150 0.109 1.44 6 11 rs9480754 G 0.0022 1.33 0.0060 2.00 × 10⁻⁴ 0.290 0.251 1.22 6 11 rs7773295 T 0.0026 1.28 0.028 8.00 × 10⁻⁴ 0.225 0.184 1.28 7 12 rs10243170 G 0.0030 0.68 0.0046 2.00 × 10⁻⁴ 0.120 0.130 0.91 7 12 rs7778636 A 0.022 0.63 0.0039 9.00 × 10⁻⁴ 0.085 0.088 0.96 9 13 rs10758593 A 8.62 × 10⁻⁴ 1.22 0.037 4.00 × 10⁻⁴ 0.492 0.426 1.30 9 13 rs10758594 A 0.0014 1.21 0.041 6.00 × 10⁻⁴ 0.513 0.451 1.28 9 14 rs824265 C 0.0092 0.61 0.0017 2.00 × 10⁻⁴ 0.104 0.123 0.83 9 14 rs824241 A 0.0079 0.67 0.0061 5.00 × 10⁻⁴ 0.108 0.127 0.83 10 15 rs4918487 T 0.0064 1.39 0.011 7.00 × 10⁻⁴ 0.202 0.153 1.40 10 15 rs7917093 A 0.0079 1.39 0.011 9.00 × 10⁻⁴ 0.204 0.156 1.39 11 16 rs4754458 A 0.0019 0.72 3.34 × 10⁻³ 8.14 × 10⁻⁵ 0.230 0.242 0.94 11 16 rs12790005 C 2.47 × 10⁻³ 1.74 2.45 × 10⁻³ 7.88 × 10⁻⁵ 0.084 0.070 1.21 11 16 rs11822881 A 0.0037 1.55 0.016 6.00 × 10⁻⁴ 0.080 0.067 1.21 11 16 rs10488765 G 0.0092 1.63 6.35 × 10⁻³ 6.00 × 10⁻⁴ 0.079 0.069 1.15 12 17 rs11048030 A 8.74 × 10⁻⁴ 1.59 0.010 1.00 × 10⁻⁴ 0.102 0.080 1.31 12 17 rs7398236 C 0.0011 1.64 9.33 × 10⁻³ 1.00 × 10⁻⁴ 0.101 0.078 1.32 12 18 rs2069408 G 5.12 × 10⁻³ 1.29 0.011 6.00 × 10⁻⁴ 0.357 0.305 1.27 12 18 rs773107 G 3.20 × 10⁻⁵ 1.31 7.81 × 10⁻³ 4.05 × 10⁻⁶ 0.366 0.295 1.38 12 18 rs10876864 G 2.07 × 10⁻⁴ 1.41 2.97 × 10⁻⁴ 1.08 × 10⁻⁶ 0.458 0.388 1.34 12 18 rs1701704 C 2.46 × 10⁻⁵ 1.36 0.0016 7.16 × 10⁻⁷ 0.379 0.303 1.40 12 18 rs705708 G 7.08 × 10⁻⁴ 1.22 0.028 2.00 × 10⁻⁴ 0.507 0.461 1.21 15 19 rs1424695 A 3.34 × 10⁻³ 0.74 0.0021 8.94 × 10⁻⁵ 0.390 0.422 0.88 15 19 rs1048048 T 2.31 × 10⁻⁴ 0.76 4.56 × 10⁻³ 1.55 × 10⁻⁵ 0.300 0.335 0.85 16 20 rs151230 T 0.013 1.44 6.04 × 10⁻³ 8.00 × 10⁻⁴ 0.161 0.139 1.19 16 20 rs9924471 T 0.0040 1.34 0.013 6.00 × 10⁻⁴ 0.208 0.175 1.24 18 21 rs543347 T 1.37 × 10⁻³ 0.70 4.67 × 10⁻³ 8.27 × 10⁻⁵ 0.111 0.147 0.72 18 21 rs540101 A 1.78 × 10⁻³ 0.71 6.43 × 10⁻³ 1.00 × 10⁻⁴ 0.111 0.147 0.72 19 22 rs602662 G 4.48 × 10⁻⁴ 0.74 1.82 × 10⁻³ 1.23 × 10⁻⁵ 0.450 0.491 0.85 19 22 rs485186 T 1.86 × 10⁻⁴ 0.75 2.31 × 10⁻³ 6.73 × 10⁻⁶ 0.445 0.490 0.83 19 22 rs504963 C 5.09 × 10⁻⁴ 0.75 2.04 × 10⁻³ 1.54 × 10⁻⁵ 0.449 0.491 0.84 20 23 rs6076595 C 0.0019 0.79 0.032 7.00 × 10⁻⁴ 0.184 0.232 0.75 20 23 rs8119653 G 3.89 × 10⁻³ 0.78 0.013 5.00 × 10⁻⁴ 0.252 0.316 0.73 X 24 rs12854493 A 0.018 1.67 0.0039 8.00 × 10⁻⁴ 0.189 0.169 1.15 X 24 rs5907223 T 0.00142 1.41 0.039 6.00 × 10⁻⁴ 0.238 0.191 1.32 X 24 rs7889974 G 5.55 × 10⁻⁴ 1.59 0.015 1.00 × 10⁻⁴ 0.165 0.132 1.30

TABLE 2 Stage 2 results for locus 18 on chromosome 12q13. T:U TDT TDT CHR SNP TDT OR Chi-square TDT P 12 rs10876864 678:550 1.233 13.34 2.60 × 10⁻⁴ 12 rs1701704 635:506 1.255 14.58 1.34 × 10⁻⁴ 12 rs773107 609:491 1.24 12.66 3.74 × 10⁻⁴

TABLE 3 All HapMap SNPs in the linkage disequilibrium block that have r2 > 0.5 in CEPH Utah Caucasians (CEU) to the three SNPs on 12q13 (rs10876864, rs1701704 and rs773107). #pos1 pos2 pop marker1 marker2 D′ r² 54660962 54655773 CEU rs773109 rs773107 1 0.959 54670954 54655773 CEU rs705698 rs773107 1 0.959 54676903 54655773 CEU rs705702 rs773107 1 0.959 54656178 54655773 CEU rs773108 rs773107 1 0.957 54721679 54655773 CEU rs705704 rs773107 0.957 0.877 54689844 54655773 CEU rs772921 rs773107 0.957 0.844 54698754 54655773 CEU rs1701704 rs773107 0.957 0.844 54703195 54655773 CEU rs2456973 rs773107 0.957 0.843 54768447 54655773 CEU rs2292239 rs773107 0.957 0.81 54766850 54655773 CEU rs877636 rs773107 0.954 0.801 54665327 54655773 CEU rs773114 rs773107 1 0.655 54665694 54655773 CEU rs1873914 rs773107 1 0.655 54687352 54655773 CEU rs10876864 rs773107 0.951 0.615 54756892 54655773 CEU rs11171739 rs773107 0.95 0.571 54763961 54655773 CEU rs2271194 rs773107 0.95 0.571 54689844 54698754 CEU rs772921 rs1701704 1 1 54703195 54698754 CEU rs2456973 rs1701704 1 1 54721679 54698754 CEU rs705704 rs1701704 1 1 54768447 54698754 CEU rs2292239 rs1701704 0.959 0.884 54660962 54698754 CEU rs773109 rs1701704 0.958 0.882 54676903 54698754 CEU rs705702 rs1701704 0.958 0.882 54670954 54698754 CEU rs705698 rs1701704 0.958 0.882 54766850 54698754 CEU rs877636 rs1701704 0.957 0.878 54656178 54698754 CEU rs773108 rs1701704 0.956 0.876 54756892 54698754 CEU rs11171739 rs1701704 0.954 0.624 54763961 54698754 CEU rs2271194 rs1701704 0.953 0.624 54665327 54698754 CEU rs773114 rs1701704 0.908 0.587 54665694 54698754 CEU rs1873914 rs1701704 0.908 0.587 54794676 54698754 CEU rs4759228 rs1701704 0.804 0.501 54665327 54687352 CEU rs773114 rs10876864 0.963 0.895 54665694 54687352 CEU rs1873914 rs10876864 0.963 0.895 54756892 54687352 CEU rs11171739 rs10876864 0.963 0.862 54763961 54687352 CEU rs2271194 rs10876864 0.963 0.862 54721679 54687352 CEU rs705704 rs10876864 1 0.703 54656178 54687352 CEU rs773108 rs10876864 0.952 0.681 54689844 54687352 CEU rs772921 rs10876864 0.955 0.672 54698754 54687352 CEU rs1701704 rs10876864 0.955 0.672 54703195 54687352 CEU rs2456973 rs10876864 0.954 0.669 54660962 54687352 CEU rs773109 rs10876864 0.953 0.643 54676903 54687352 CEU rs705702 rs10876864 0.953 0.643 54670954 54687352 CEU rs705698 rs10876864 0.953 0.643 54768447 54687352 CEU rs2292239 rs10876864 0.867 0.577 54766850 54687352 CEU rs877636 rs10876864 0.861 0.562

Example II

To determine if mRNA expression of any of the six genes at the 12q13 locus were under regulatory influence of the SNPs that are present on the HumanHap550 SNP chip and showing association with T1D, the “mRNA by SNP Browser” program was used to query the genes residing within the 12q13 locus with respect to correlation with expression quantitative trait loci (eQTLs). This program can be found on the world wide web at: (sph.umich.edu/csg/liang/asthma). A strong correlation was observed between the most significant T1D associated SNPs and eQTLs for the RPS26 gene (see Table 4). None of the other five genes demonstrated eQTL signals.

TABLE 4 eQTL correlation with two Affymetrix probes for the RPS26 gene and the most significant T1D associated SNPs at the 12q13 locus. Affymetrix Probe SNP ID Effect H2 LOD P-value 217753_s_at rs10876864 −1.141 63.97 46.38 2.30 × 10⁻⁴⁸ 234885_at rs10876864 −0.57 15.98 11.65 2.40 × 10⁻¹³ 217753_s_at rs1701704 −1.024 47.75 33.04 5.80 × 10⁻³⁵ 234885_at rs1701704 −0.532 12.88 9.14 8.80 × 10⁻¹¹ 217753_s_at rs773107 −0.941 39.77 27.88 9.20 × 10⁻³⁰ 234885_at rs773107 −0.474 10.06 7.24 7.70 × 10⁻⁹ 

These data show that the RPS26 gene is under strong regulatory influence of the SNPs that associate with T1D at the 12q13 locus. While all six genes may contribute to development of T1D, these data suggest that the RPS26 gene may be most influential in the pathogenesis of T1D. Tables 5-10 below contain candidate siRNA constructs directed to the genes at chromosome 12q13.

TABLE 5 Candidate siRNAs for CDK2, SEQ ID NOs: 12-251 are based on NM_052827 and SEQ ID NOs: 252-488 are based on NM_001798. SEQ ID NO: 12 CCAGAGGCCCCGCCCCUGCtt SEQ ID NO: 13 GUUGCCGCCUCCCACCGAGtt SEQ ID NO: 14 UGGCCAACUUGAAACAAUGtt SEQ ID NO: 15 UCUUGUCAAUUUGGCCAACtt SEQ ID NO: 16 ACCUCUCGCUCUUGUCAAUtt SEQ ID NO: 17 CGCAGUAUACCUCUCGCUCtt SEQ ID NO: 18 CUUUUCCACCUUUUGGAAGtt SEQ ID NO: 19 CUCCGAUCUUUUCCACCUUtt SEQ ID NO: 20 CUCUCCGAUCUUUUCCACCtt SEQ ID NO: 21 ACGUGCCCUCUCCGAUCUUtt SEQ ID NO: 22 GUACGUGCCCUCUCCGAUCtt SEQ ID NO: 23 CGUCAACUUGUUUCUGGCUtt SEQ ID NO: 24 ACCUCUCCCGUCAACUUGUtt SEQ ID NO: 25 CACCACCUCUCCCGUCAACtt SEQ ID NO: 26 AGUGUCCAGGCGGAUUUUCtt SEQ ID NO: 27 CUCAGUGUCCAGGCGGAUUtt SEQ ID NO: 28 GUCUCAGUGUCCAGGCGGAtt SEQ ID NO: 29 AUUAGGAUGGUUAAGCUCCtt SEQ ID NO: 30 CUUGACAAUAUUAGGAUGGtt SEQ ID NO: 31 AUCCAGCAGCUUGACAAUAtt SEQ ID NO: 32 GUGAAUGACAUCCAGCAGCtt SEQ ID NO: 33 AAACCAGGUAGAGUUUAUUtt SEQ ID NO: 34 AAAAACCAGGUAGAGUUUAtt SEQ ID NO: 35 UUCAAAAACCAGGUAGAGUtt SEQ ID NO: 36 UGAGAUCUUGGUGCAGAAAtt SEQ ID NO: 37 CCAUGAAUUUCUUGAGAUCtt SEQ ID NO: 38 AGAGGCAUCCAUGAAUUUCtt SEQ ID NO: 39 AGCAGAGGCAUCCAUGAAUtt SEQ ID NO: 40 CAGCUGGAACAGAUAGCUCtt SEQ ID NO: 41 AAUAAGCAGAUUCUGAGGUtt SEQ ID NO: 42 CUCUGUGUUAAUAAGCAGAtt SEQ ID NO: 43 CUUGAUGGCCCCCUCUGUGtt SEQ ID NO: 44 UAGUCCAAAGUCUGCUAGCtt SEQ ID NO: 45 CCACUUGGGGAAACUUGGCtt SEQ ID NO: 46 CGGGCCCACUUGGGGAAACtt SEQ ID NO: 47 AAAAUCUUGCCGGGCCCACtt SEQ ID NO: 48 GUACAACUUUACUAAAAUCtt SEQ ID NO: 49 AUCCAGGGGAGGUACAACUtt SEQ ID NO: 50 AUAACAAGCUCCGUCCAUCtt SEQ ID NO: 51 UAGGGUCGUAGUGCAGCAUtt SEQ ID NO: 52 CUUGGCCGAAAUCCGCUUGtt SEQ ID NO: 53 UGCCUUGGCCGAAAUCCGCtt SEQ ID NO: 54 AGGGUGAGCCAGGGCUGCCtt SEQ ID NO: 55 UCGAAGAUGGGGUACUGGCtt SEQ ID NO: 56 UGAGAUUAGGGCUGGGGGCtt SEQ ID NO: 57 ACUGGAGGAGAGGGUGAGAtt SEQ ID NO: 58 GGUGAGUGUUUAAGGCAAGtt SEQ ID NO: 59 AAGACUAGAAGGUGAGUGUtt SEQ ID NO: 60 CACCCCUGUAUUCCCAGAGtt SEQ ID NO: 61 CCCCCCUUUCACCCCUGUAtt SEQ ID NO: 62 UUUUCACUGGUUCCCCCCUtt SEQ ID NO: 63 UUCCUUUCAUUUUCACUGGtt SEQ ID NO: 64 ACUGAAACUUCCUUUCAUUtt SEQ ID NO: 65 AUACUGAAACUUCCUUUCAtt SEQ ID NO: 66 UCUAAUACUGAAACUUCCUtt SEQ ID NO: 67 GUGCAUCUAAUACUGAAACtt SEQ ID NO: 68 AAGGGUGGUGGAGGCUAACtt SEQ ID NO: 69 UAUUUUUAUACCAACCCUCtt SEQ ID NO: 70 GGCUUUUUUAAAAUUAUUUtt SEQ ID NO: 71 AAGGCUUUUUUAAAAUUAUtt SEQ ID NO: 72 UAGGAAGGCUUUUUUAAAAtt SEQ ID NO: 73 AACGUGUAGGAAGGCUUUUtt SEQ ID NO: 74 CUAACGUGUAGGAAGGCUUtt SEQ ID NO: 75 AUCUAACGUGUAGGAAGGCtt SEQ ID NO: 76 AUUAUGGGGCAUUCAGAGAtt SEQ ID NO: 77 AAAUAAUAAUUAUGGGGCAtt SEQ ID NO: 78 CAAACACUGGAAAUAAUAAtt SEQ ID NO: 79 CAUUGUGGCAGCAGGAGGCtt SEQ ID NO: 80 CAUUUGGCCUUUAUAAACAtt SEQ ID NO: 81 CCCCGCUAUCAUUUGGCCUtt SEQ ID NO: 82 ACUUAGCCCCCGCUAUCAUtt SEQ ID NO: 83 GGUUCUCAAAAGCACCAACtt SEQ ID NO: 84 GUGGUUUUGUUUUACUUGGtt SEQ ID NO: 85 CCCAGUGGUUUUGUUUUACtt SEQ ID NO: 86 UCCUCCCAGUGGUUUUGUUtt SEQ ID NO: 87 ACUCCUCCCAGUGGUUUUGtt SEQ ID NO: 88 UAGACUCCUCCCAGUGGUUtt SEQ ID NO: 89 AAUAGACUCCUCCCAGUGGtt SEQ ID NO: 90 AUUUUUUCAACCGAAUUCUtt SEQ ID NO: 91 AUCUAUUUUUUCAACCGAAtt SEQ ID NO: 92 AACUGAUUGGAUCUAUUUUtt SEQ ID NO: 93 UAAACUGAUUGGAUCUAUUtt SEQ ID NO: 94 UAUAAACUGAUUGGAUCUAtt SEQ ID NO: 95 UAACUAGGGUAUAAACUGAtt SEQ ID NO: 96 UCUUCAGUCUCCCAGCCUAtt SEQ ID NO: 97 GCCCCACCCGGGCUGAGUCtt SEQ ID NO: 98 GGACUGGGGCCAAUCAUUUtt SEQ ID NO: 99 GGGGACUGGGGCCAAUCAUtt SEQ ID NO: 100 UGUCUCAGGGCCUCCCAGAtt SEQ ID NO: 101 GCCAUGGUGAAGCAAUAGAtt SEQ ID NO: 102 ACUAAAAGGAAGAGAAAAAtt SEQ ID NO: 103 AAAAUGGGAUCAGGGAUCCtt SEQ ID NO: 104 AUGAUGCCUAAACCCUAACtt SEQ ID NO: 105 CCCUGAAAAAGUGUCAGCAtt SEQ ID NO: 106 UUCUUUUAAAGAAAUAUUUtt SEQ ID NO: 107 CCUUCUUUUAAAGAAAUAUtt SEQ ID NO: 108 AUAAUUGUUCAUCCUUCUUtt SEQ ID NO: 109 AUAUAAUUGUUCAUCCUUCtt SEQ ID NO: 110 UAAAUAUAAUUGUUCAUCCtt SEQ ID NO: 111 UGAAAUAUAAAUAUAAUUGtt SEQ ID NO: 112 ACCUGAAAUAUAAAUAUAAtt SEQ ID NO: 113 AAAAAAGCCAACUCUACUAtt SEQ ID NO: 114 UUUUUUUUUAGCACUGUCAtt SEQ ID NO: 115 AAAAAAAUGCUUUUUUUUUtt SEQ ID NO: 116 AAAAAAAAAUGCUUUUUUUtt SEQ ID NO: 117 UAAAAAAAAAAUGCUUUUUtt SEQ ID NO: 118 CAUAAAAAAAAAAUGCUUUtt SEQ ID NO: 119 AUCAUAAAAAAAAAAUGCUtt SEQ ID NO: 120 AACUAAAUUACAAAUAACGtt SEQ ID NO: 121 UAAUGAGCUACAAACUAAAtt SEQ ID NO: 122 UAAAACUAGGCACAUUUUUtt SEQ ID NO: 123 UAUAAAACUAGGCACAUUUtt SEQ ID NO: 124 UUUAUAAAACUAGGCACAUtt SEQ ID NO: 125 UUGUUUUUUUUUUUUUUUUtt SEQ ID NO: 126 UUUUGUUUUUUUUUUUUUUtt SEQ ID NO: 127 UUUUUUGUUUUUUUUUUUUtt SEQ ID NO: 128 UUUUUUUUGUUUUUUUUUUtt SEQ ID NO: 129 UUUUUUUUUUGUUUUUUUUtt SEQ ID NO: 130 UUUUUUUUUUUUGUUUUUUtt SEQ ID NO: 131 UUUUUUUUUUUUUUGUUUUtt SEQ ID NO: 132 GCAGGGGCGGGGCCUCUGGtt SEQ ID NO: 133 CUCGGUGGGAGGCGGCAACtt SEQ ID NO: 134 CAUUGUUUCAAGUUGGCCAtt SEQ ID NO: 135 GUUGGCCAAAUUGACAAGAtt SEQ ID NO: 136 AUUGACAAGAGCGAGAGGUtt SEQ ID NO: 137 GAGCGAGAGGUAUACUGCGtt SEQ ID NO: 138 CUUCCAAAAGGUGGAAAAGtt SEQ ID NO: 139 AAGGUGGAAAAGAUCGGAGtt SEQ ID NO: 140 GGUGGAAAAGAUCGGAGAGtt SEQ ID NO: 141 AAGAUCGGAGAGGGCACGUtt SEQ ID NO: 142 GAUCGGAGAGGGCACGUACtt SEQ ID NO: 143 AGCCAGAAACAAGUUGACGtt SEQ ID NO: 144 ACAAGUUGACGGGAGAGGUtt SEQ ID NO: 145 GUUGACGGGAGAGGUGGUGtt SEQ ID NO: 146 GAAAAUCCGCCUGGACACUtt SEQ ID NO: 147 AAUCCGCCUGGACACUGAGtt SEQ ID NO: 148 UCCGCCUGGACACUGAGACtt SEQ ID NO: 149 GGAGCUUAACCAUCCUAAUtt SEQ ID NO: 150 CCAUCCUAAUAUUGUCAAGtt SEQ ID NO: 151 UAUUGUCAAGCUGCUGGAUtt SEQ ID NO: 152 GCUGCUGGAUGUCAUUCACtt SEQ ID NO: 153 AAUAAACUCUACCUGGUUUtt SEQ ID NO: 154 UAAACUCUACCUGGUUUUUtt SEQ ID NO: 155 ACUCUACCUGGUUUUUGAAtt SEQ ID NO: 156 UUUCUGCACCAAGAUCUCAtt SEQ ID NO: 157 GAUCUCAAGAAAUUCAUGGtt SEQ ID NO: 158 GAAAUUCAUGGAUGCCUCUtt SEQ ID NO: 159 AUUCAUGGAUGCCUCUGCUtt SEQ ID NO: 160 GAGCUAUCUGUUCCAGCUGtt SEQ ID NO: 161 ACCUCAGAAUCUGCUUAUUtt SEQ ID NO: 162 UCUGCUUAUUAACACAGAGtt SEQ ID NO: 163 CACAGAGGGGGCCAUCAAGtt SEQ ID NO: 164 GCUAGCAGACUUUGGACUAtt SEQ ID NO: 165 GCCAAGUUUCCCCAAGUGGtt SEQ ID NO: 166 GUUUCCCCAAGUGGGCCCGtt SEQ ID NO: 167 GUGGGCCCGGCAAGAUUUUtt SEQ ID NO: 168 GAUUUUAGUAAAGUUGUACtt SEQ ID NO: 169 AGUUGUACCUCCCCUGGAUtt SEQ ID NO: 170 GAUGGACGGAGCUUGUUAUtt SEQ ID NO: 171 AUGCUGCACUACGACCCUAtt SEQ ID NO: 172 CAAGCGGAUUUCGGCCAAGtt SEQ ID NO: 173 GCGGAUUUCGGCCAAGGCAtt SEQ ID NO: 174 GGCAGCCCUGGCUCACCCUtt SEQ ID NO: 175 GCCAGUACCCCAUCUUCGAtt SEQ ID NO: 176 GCCCCCAGCCCUAAUCUCAtt SEQ ID NO: 177 UCUCACCCUCUCCUCCAGUtt SEQ ID NO: 178 CUUGCCUUAAACACUCACCtt SEQ ID NO: 179 ACACUCACCUUCUAGUCUUtt SEQ ID NO: 180 CUCUGGGAAUACAGGGGUGtt SEQ ID NO: 181 UACAGGGGUGAAAGGGGGGtt SEQ ID NO: 182 AGGGGGGAACCAGUGAAAAtt SEQ ID NO: 183 CCAGUGAAAAUGAAAGGAAtt SEQ ID NO: 184 AAUGAAAGGAAGUUUCAGUtt SEQ ID NO: 185 UGAAAGGAAGUUUCAGUAUtt SEQ ID NO: 186 AGGAAGUUUCAGUAUUAGAtt SEQ ID NO: 187 GUUUCAGUAUUAGAUGCACtt SEQ ID NO: 188 GUUAGCCUCCACCACCCUUtt SEQ ID NO: 189 GAGGGUUGGUAUAAAAAUAtt SEQ ID NO: 190 AAAUAAUUUUAAAAAAGCCtt SEQ ID NO: 191 AUAAUUUUAAAAAAGCCUUtt SEQ ID NO: 192 UUUUAAAAAAGCCUUCCUAtt SEQ ID NO: 193 AAAAGCCUUCCUACACGUUtt SEQ ID NO: 194 AAGCCUUCCUACACGUUAGtt SEQ ID NO: 195 GCCUUCCUACACGUUAGAUtt SEQ ID NO: 196 UCUCUGAAUGCCCCAUAAUtt SEQ ID NO: 197 UGCCCCAUAAUUAUUAUUUtt SEQ ID NO: 198 UUAUUAUUUCCAGUGUUUGtt SEQ ID NO: 199 GCCUCCUGCUGCCACAAUGtt SEQ ID NO: 200 UGUUUAUAAAGGCCAAAUGtt SEQ ID NO: 201 AGGCCAAAUGAUAGCGGGGtt SEQ ID NO: 202 AUGAUAGCGGGGGCUAAGUtt SEQ ID NO: 203 GUUGGUGCUUUUGAGAACCtt SEQ ID NO: 204 CCAAGUAAAACAAAACCACtt SEQ ID NO: 205 GUAAAACAAAACCACUGGGtt SEQ ID NO: 206 AACAAAACCACUGGGAGGAtt SEQ ID NO: 207 CAAAACCACUGGGAGGAGUtt SEQ ID NO: 208 AACCACUGGGAGGAGUCUAtt SEQ ID NO: 209 CCACUGGGAGGAGUCUAUUtt SEQ ID NO: 210 AGAAUUCGGUUGAAAAAAUtt SEQ ID NO: 211 UUCGGUUGAAAAAAUAGAUtt SEQ ID NO: 212 AAAAUAGAUCCAAUCAGUUtt SEQ ID NO: 213 AAUAGAUCCAAUCAGUUUAtt SEQ ID NO: 214 UAGAUCCAAUCAGUUUAUAtt SEQ ID NO: 215 UCAGUUUAUACCCUAGUUAtt SEQ ID NO: 216 UAGGCUGGGAGACUGAAGAtt SEQ ID NO: 217 GACUCAGCCCGGGUGGGGCtt SEQ ID NO: 218 AAAUGAUUGGCCCCAGUCCtt SEQ ID NO: 219 AUGAUUGGCCCCAGUCCCCtt SEQ ID NO: 220 UCUGGGAGGCCCUGAGACAtt SEQ ID NO: 221 UCUAUUGCUUCACCAUGGCtt SEQ ID NO: 222 UUUUUCUCUUCCUUUUAGUtt SEQ ID NO: 223 GGAUCCCUGAUCCCAUUUUtt SEQ ID NO: 224 GUUAGGGUUUAGGCAUCAUtt SEQ ID NO: 225 UGCUGACACUUUUUCAGGGtt SEQ ID NO: 226 AAAUAUUUCUUUAAAAGAAtt SEQ ID NO: 227 AUAUUUCUUUAAAAGAAGGtt SEQ ID NO: 228 AAGAAGGAUGAACAAUUAUtt SEQ ID NO: 229 GAAGGAUGAACAAUUAUAUtt SEQ ID NO: 230 GGAUGAACAAUUAUAUUUAtt SEQ ID NO: 231 CAAUUAUAUUUAUAUUUCAtt SEQ ID NO: 232 UUAUAUUUAUAUUUCAGGUtt SEQ ID NO: 233 UAGUAGAGUUGGCUUUUUUtt SEQ ID NO: 234 UGACAGUGCUAAAAAAAAAtt SEQ ID NO: 235 AAAAAAAAAGCAUUUUUUUtt SEQ ID NO: 236 AAAAAAAGCAUUUUUUUUUtt SEQ ID NO: 237 AAAAAGCAUUUUUUUUUUAtt SEQ ID NO: 238 AAAGCAUUUUUUUUUUAUGtt SEQ ID NO: 239 AGCAUUUUUUUUUUAUGAUtt SEQ ID NO: 240 CGUUAUUUGUAAUUUAGUUtt SEQ ID NO: 241 UUUAGUUUGUAGCUCAUUAtt SEQ ID NO: 242 AAAAAUGUGCCUAGUUUUAtt SEQ ID NO: 243 AAAUGUGCCUAGUUUUAUAtt SEQ ID NO: 244 AUGUGCCUAGUUUUAUAAAtt SEQ ID NO: 245 AAAAAAAAAAAAAAAACAAtt SEQ ID NO: 246 AAAAAAAAAAAAAACAAAAtt SEQ ID NO: 247 AAAAAAAAAAAACAAAAAAtt SEQ ID NO: 248 AAAAAAAAAACAAAAAAAAtt SEQ ID NO: 249 AAAAAAAACAAAAAAAAAAtt SEQ ID NO: 250 AAAAAACAAAAAAAAAAAAtt SEQ ID NO: 251 AAAACAAAAAAAAAAAAAAtt SEQ ID NO: 252 CCAGAGGCCCCGCCCCUGCtt SEQ ID NO: 253 GUUGCCGCCUCCCACCGAGtt SEQ ID NO: 254 UGGCCAACUUGAAACAAUGtt SEQ ID NO: 255 UCUUGUCAAUUUGGCCAACtt SEQ ID NO: 256 ACCUCUCGCUCUUGUCAAUtt SEQ ID NO: 257 CGCAGUAUACCUCUCGCUCtt SEQ ID NO: 258 CUUUUCCACCUUUUGGAAGtt SEQ ID NO: 259 CUCCGAUCUUUUCCACCUUtt SEQ ID NO: 260 CUCUCCGAUCUUUUCCACCtt SEQ ID NO: 261 ACGUGCCCUCUCCGAUCUUtt SEQ ID NO: 262 GUACGUGCCCUCUCCGAUCtt SEQ ID NO: 263 CGUCAACUUGUUUCUGGCUtt SEQ ID NO: 264 ACCUCUCCCGUCAACUUGUtt SEQ ID NO: 265 CACCACCUCUCCCGUCAACtt SEQ ID NO: 266 AGUGUCCAGGCGGAUUUUCtt SEQ ID NO: 267 CUCAGUGUCCAGGCGGAUUtt SEQ ID NO: 268 GUCUCAGUGUCCAGGCGGAtt SEQ ID NO: 269 AUUAGGAUGGUUAAGCUCCtt SEQ ID NO: 270 CUUGACAAUAUUAGGAUGGtt SEQ ID NO: 271 AUCCAGCAGCUUGACAAUAtt SEQ ID NO: 272 GUGAAUGACAUCCAGCAGCtt SEQ ID NO: 273 AAACCAGGUAGAGUUUAUUtt SEQ ID NO: 274 AAAAACCAGGUAGAGUUUAtt SEQ ID NO: 275 UUCAAAAACCAGGUAGAGUtt SEQ ID NO: 276 UGAGAUCUUGGUGCAGAAAtt SEQ ID NO: 277 CCAUGAAUUUCUUGAGAUCtt SEQ ID NO: 278 AGAGGCAUCCAUGAAUUUCtt SEQ ID NO: 279 AGCAGAGGCAUCCAUGAAUtt SEQ ID NO: 280 CAGCUGGAACAGAUAGCUCtt SEQ ID NO: 281 AAUAAGCAGAUUCUGAGGUtt SEQ ID NO: 282 CUCUGUGUUAAUAAGCAGAtt SEQ ID NO: 283 CUUGAUGGCCCCCUCUGUGtt SEQ ID NO: 284 UAGUCCAAAGUCUGCUAGCtt SEQ ID NO: 285 AUUUGCAGCCCAGGAGGAUtt SEQ ID NO: 286 CACAGCUGUGGAAUAAUAUtt SEQ ID NO: 287 CCACUUGGGGAAACUUGGCtt SEQ ID NO: 288 CGGGCCCACUUGGGGAAACtt SEQ ID NO: 289 AAAAUCUUGCCGGGCCCACtt SEQ ID NO: 290 GUACAACUUUACUAAAAUCtt SEQ ID NO: 291 AUCCAGGGGAGGUACAACUtt SEQ ID NO: 292 AUAACAAGCUCCGUCCAUCtt SEQ ID NO: 293 UAGGGUCGUAGUGCAGCAUtt SEQ ID NO: 294 CUUGGCCGAAAUCCGCUUGtt SEQ ID NO: 295 UGCCUUGGCCGAAAUCCGCtt SEQ ID NO: 296 AGGGUGAGCCAGGGCUGCCtt SEQ ID NO: 297 UCGAAGAUGGGGUACUGGCtt SEQ ID NO: 298 UGAGAUUAGGGCUGGGGGCtt SEQ ID NO: 299 ACUGGAGGAGAGGGUGAGAtt SEQ ID NO: 300 GGUGAGUGUUUAAGGCAAGtt SEQ ID NO: 301 AAGACUAGAAGGUGAGUGUtt SEQ ID NO: 302 CACCCCUGUAUUCCCAGAGtt SEQ ID NO: 303 CCCCCCUUUCACCCCUGUAtt SEQ ID NO: 304 UUUUCACUGGUUCCCCCCUtt SEQ ID NO: 305 UUCCUUUCAUUUUCACUGGtt SEQ ID NO: 306 ACUGAAACUUCCUUUCAUUtt SEQ ID NO: 307 AUACUGAAACUUCCUUUCAtt SEQ ID NO: 308 UCUAAUACUGAAACUUCCUtt SEQ ID NO: 309 GUGCAUCUAAUACUGAAACtt SEQ ID NO: 310 AAGGGUGGUGGAGGCUAACtt SEQ ID NO: 311 UAUUUUUAUACCAACCCUCtt SEQ ID NO: 312 GGCUUUUUUAAAAUUAUUUtt SEQ ID NO: 313 AAGGCUUUUUUAAAAUUAUtt SEQ ID NO: 314 UAGGAAGGCUUUUUUAAAAtt SEQ ID NO: 315 AACGUGUAGGAAGGCUUUUtt SEQ ID NO: 316 CUAACGUGUAGGAAGGCUUtt SEQ ID NO: 317 AUCUAACGUGUAGGAAGGCtt SEQ ID NO: 318 AUUAUGGGGCAUUCAGAGAtt SEQ ID NO: 319 AAAUAAUAAUUAUGGGGCAtt SEQ ID NO: 320 CAAACACUGGAAAUAAUAAtt SEQ ID NO: 321 CAUUGUGGCAGCAGGAGGCtt SEQ ID NO: 322 CAUUUGGCCUUUAUAAACAtt SEQ ID NO: 323 CCCCGCUAUCAUUUGGCCUtt SEQ ID NO: 324 ACUUAGCCCCCGCUAUCAUtt SEQ ID NO: 325 GGUUCUCAAAAGCACCAACtt SEQ ID NO: 326 GUGGUUUUGUUUUACUUGGtt SEQ ID NO: 327 CCCAGUGGUUUUGUUUUACtt SEQ ID NO: 328 UCCUCCCAGUGGUUUUGUUtt SEQ ID NO: 329 ACUCCUCCCAGUGGUUUUGtt SEQ ID NO: 330 UAGACUCCUCCCAGUGGUUtt SEQ ID NO: 331 AAUAGACUCCUCCCAGUGGtt SEQ ID NO: 332 AUUUUUUCAACCGAAUUCUtt SEQ ID NO: 333 AUCUAUUUUUUCAACCGAAtt SEQ ID NO: 334 AACUGAUUGGAUCUAUUUUtt SEQ ID NO: 335 UAAACUGAUUGGAUCUAUUtt SEQ ID NO: 336 UAUAAACUGAUUGGAUCUAtt SEQ ID NO: 337 UAACUAGGGUAUAAACUGAtt SEQ ID NO: 338 UCUUCAGUCUCCCAGCCUAtt SEQ ID NO: 339 GCCCCACCCGGGCUGAGUCtt SEQ ID NO: 340 GGACUGGGGCCAAUCAUUUtt SEQ ID NO: 341 GGGGACUGGGGCCAAUCAUtt SEQ ID NO: 342 UGUCUCAGGGCCUCCCAGAtt SEQ ID NO: 343 GCCAUGGUGAAGCAAUAGAtt SEQ ID NO: 344 ACUAAAAGGAAGAGAAAAAtt SEQ ID NO: 345 AAAAUGGGAUCAGGGAUCCtt SEQ ID NO: 346 AUGAUGCCUAAACCCUAACtt SEQ ID NO: 347 CCCUGAAAAAGUGUCAGCAtt SEQ ID NO: 348 UUCUUUUAAAGAAAUAUUUtt SEQ ID NO: 349 CCUUCUUUUAAAGAAAUAUtt SEQ ID NO: 350 AUAAUUGUUCAUCCUUCUUtt SEQ ID NO: 351 AUAUAAUUGUUCAUCCUUCtt SEQ ID NO: 352 UAAAUAUAAUUGUUCAUCCtt SEQ ID NO: 353 UGAAAUAUAAAUAUAAUUGtt SEQ ID NO: 354 ACCUGAAAUAUAAAUAUAAtt SEQ ID NO: 355 AAAAAAGCCAACUCUACUAtt SEQ ID NO: 356 UUUUUUUUUAGCACUGUCAtt SEQ ID NO: 357 AAAAAAAUGCUUUUUUUUUtt SEQ ID NO: 358 AAAAAAAAAUGCUUUUUUUtt SEQ ID NO: 359 UAAAAAAAAAAUGCUUUUUtt SEQ ID NO: 360 CAUAAAAAAAAAAUGCUUUtt SEQ ID NO: 361 AUCAUAAAAAAAAAAUGCUtt SEQ ID NO: 362 AACUAAAUUACAAAUAACGtt SEQ ID NO: 363 UAAUGAGCUACAAACUAAAtt SEQ ID NO: 364 UAAAACUAGGCACAUUUUUtt SEQ ID NO: 365 UAUAAAACUAGGCACAUUUtt SEQ ID NO: 366 UUUAUAAAACUAGGCACAUtt SEQ ID NO: 367 UUGUUUUUUUUUUUUUUUUtt SEQ ID NO: 368 UUUUGUUUUUUUUUUUUUUtt SEQ ID NO: 369 UUUUUUGUUUUUUUUUUUUtt SEQ ID NO: 370 UUUUUUUUGUUUUUUUUUUtt SEQ ID NO: 371 UUUUUUUUUUGUUUUUUUUtt SEQ ID NO: 372 UUUUUUUUUUUUGUUUUUUtt SEQ ID NO: 373 UUUUUUUUUUUUUUGUUUUtt SEQ ID NO: 374 GCAGGGGCGGGGCCUCUGGtt SEQ ID NO: 375 CUCGGUGGGAGGCGGCAACtt SEQ ID NO: 376 CAUUGUUUCAAGUUGGCCAtt SEQ ID NO: 377 GUUGGCCAAAUUGACAAGAtt SEQ ID NO: 378 AUUGACAAGAGCGAGAGGUtt SEQ ID NO: 379 GAGCGAGAGGUAUACUGCGtt SEQ ID NO: 380 CUUCCAAAAGGUGGAAAAGtt SEQ ID NO: 381 AAGGUGGAAAAGAUCGGAGtt SEQ ID NO: 382 GGUGGAAAAGAUCGGAGAGtt SEQ ID NO: 383 AAGAUCGGAGAGGGCACGUtt SEQ ID NO: 384 GAUCGGAGAGGGCACGUACtt SEQ ID NO: 385 AGCCAGAAACAAGUUGACGtt SEQ ID NO: 386 ACAAGUUGACGGGAGAGGUtt SEQ ID NO: 387 GUUGACGGGAGAGGUGGUGtt SEQ ID NO: 388 GAAAAUCCGCCUGGACACUtt SEQ ID NO: 389 AAUCCGCCUGGACACUGAGtt SEQ ID NO: 390 UCCGCCUGGACACUGAGACtt SEQ ID NO: 391 GGAGCUUAACCAUCCUAAUtt SEQ ID NO: 392 CCAUCCUAAUAUUGUCAAGtt SEQ ID NO: 393 UAUUGUCAAGCUGCUGGAUtt SEQ ID NO: 394 GCUGCUGGAUGUCAUUCACtt SEQ ID NO: 395 AAUAAACUCUACCUGGUUUtt SEQ ID NO: 396 UAAACUCUACCUGGUUUUUtt SEQ ID NO: 397 ACUCUACCUGGUUUUUGAAtt SEQ ID NO: 398 UUUCUGCACCAAGAUCUCAtt SEQ ID NO: 399 GAUCUCAAGAAAUUCAUGGtt SEQ ID NO: 400 GAAAUUCAUGGAUGCCUCUtt SEQ ID NO: 401 AUUCAUGGAUGCCUCUGCUtt SEQ ID NO: 402 GAGCUAUCUGUUCCAGCUGtt SEQ ID NO: 403 ACCUCAGAAUCUGCUUAUUtt SEQ ID NO: 404 UCUGCUUAUUAACACAGAGtt SEQ ID NO: 405 CACAGAGGGGGCCAUCAAGtt SEQ ID NO: 406 GCUAGCAGACUUUGGACUAtt SEQ ID NO: 407 AUCCUCCUGGGCUGCAAAUtt SEQ ID NO: 408 AUAUUAUUCCACAGCUGUGtt SEQ ID NO: 409 GCCAAGUUUCCCCAAGUGGtt SEQ ID NO: 410 GUUUCCCCAAGUGGGCCCGtt SEQ ID NO: 411 GUGGGCCCGGCAAGAUUUUtt SEQ ID NO: 412 GAUUUUAGUAAAGUUGUACtt SEQ ID NO: 413 AGUUGUACCUCCCCUGGAUtt SEQ ID NO: 414 GAUGGACGGAGCUUGUUAUtt SEQ ID NO: 415 AUGCUGCACUACGACCCUAtt SEQ ID NO: 416 CAAGCGGAUUUCGGCCAAGtt SEQ ID NO: 417 GCGGAUUUCGGCCAAGGCAtt SEQ ID NO: 418 GGCAGCCCUGGCUCACCCUtt SEQ ID NO: 419 GCCAGUACCCCAUCUUCGAtt SEQ ID NO: 420 GCCCCCAGCCCUAAUCUCAtt SEQ ID NO: 421 UCUCACCCUCUCCUCCAGUtt SEQ ID NO: 422 CUUGCCUUAAACACUCACCtt SEQ ID NO: 423 ACACUCACCUUCUAGUCUUtt SEQ ID NO: 424 CUCUGGGAAUACAGGGGUGtt SEQ ID NO: 425 UACAGGGGUGAAAGGGGGGtt SEQ ID NO: 426 AGGGGGGAACCAGUGAAAAtt SEQ ID NO: 427 CCAGUGAAAAUGAAAGGAAtt SEQ ID NO: 428 AAUGAAAGGAAGUUUCAGUtt SEQ ID NO: 429 UGAAAGGAAGUUUCAGUAUtt SEQ ID NO: 430 AGGAAGUUUCAGUAUUAGAtt SEQ ID NO: 431 GUUUCAGUAUUAGAUGCACtt SEQ ID NO: 432 GUUAGCCUCCACCACCCUUtt SEQ ID NO: 433 GAGGGUUGGUAUAAAAAUAtt SEQ ID NO: 434 AAAUAAUUUUAAAAAAGCCtt SEQ ID NO: 435 AUAAUUUUAAAAAAGCCUUtt SEQ ID NO: 436 UUUUAAAAAAGCCUUCCUAtt SEQ ID NO: 437 AAAAGCCUUCCUACACGUUtt SEQ ID NO: 438 AAGCCUUCCUACACGUUAGtt SEQ ID NO: 439 GCCUUCCUACACGUUAGAUtt SEQ ID NO: 440 UCUCUGAAUGCCCCAUAAUtt SEQ ID NO: 441 UGCCCCAUAAUUAUUAUUUtt SEQ ID NO: 442 UUAUUAUUUCCAGUGUUUGtt SEQ ID NO: 443 GCCUCCUGCUGCCACAAUGtt SEQ ID NO: 444 UGUUUAUAAAGGCCAAAUGtt SEQ ID NO: 445 AGGCCAAAUGAUAGCGGGGtt SEQ ID NO: 446 AUGAUAGCGGGGGCUAAGUtt SEQ ID NO: 447 GUUGGUGCUUUUGAGAACCtt SEQ ID NO: 448 CCAAGUAAAACAAAACCACtt SEQ ID NO: 449 GUAAAACAAAACCACUGGGtt SEQ ID NO: 450 AACAAAACCACUGGGAGGAtt SEQ ID NO: 451 CAAAACCACUGGGAGGAGUtt SEQ ID NO: 452 AACCACUGGGAGGAGUCUAtt SEQ ID NO: 453 CCACUGGGAGGAGUCUAUUtt SEQ ID NO: 454 AGAAUUCGGUUGAAAAAAUtt SEQ ID NO: 455 UUCGGUUGAAAAAAUAGAUtt SEQ ID NO: 456 AAAAUAGAUCCAAUCAGUUtt SEQ ID NO: 457 AAUAGAUCCAAUCAGUUUAtt SEQ ID NO: 458 UAGAUCCAAUCAGUUUAUAtt SEQ ID NO: 459 UCAGUUUAUACCCUAGUUAtt SEQ ID NO: 460 UAGGCUGGGAGACUGAAGAtt SEQ ID NO: 461 GACUCAGCCCGGGUGGGGCtt SEQ ID NO: 462 AAAUGAUUGGCCCCAGUCCtt SEQ ID NO: 463 AUGAUUGGCCCCAGUCCCCtt SEQ ID NO: 464 UCUGGGAGGCCCUGAGACAtt SEQ ID NO: 465 UCUAUUGCUUCACCAUGGCtt SEQ ID NO: 466 UUUUUCUCUUCCUUUUAGUtt SEQ ID NO: 467 GGAUCCCUGAUCCCAUUUUtt SEQ ID NO: 468 GUUAGGGUUUAGGCAUCAUtt SEQ ID NO: 469 UGCUGACACUUUUUCAGGGtt SEQ ID NO: 470 AAAUAUUUCUUUAAAAGAAtt SEQ ID NO: 471 AUAUUUCUUUAAAAGAAGGtt SEQ ID NO: 472 AAGAAGGAUGAACAAUUAUtt SEQ ID NO: 473 GAAGGAUGAACAAUUAUAUtt SEQ ID NO: 474 GGAUGAACAAUUAUAUUUAtt SEQ ID NO: 475 CAAUUAUAUUUAUAUUUCAtt SEQ ID NO: 476 UUAUAUUUAUAUUUCAGGUtt SEQ ID NO: 477 UAGUAGAGUUGGCUUUUUUtt SEQ ID NO: 478 UGACAGUGCUAAAAAAAAAtt SEQ ID NO: 479 AAAAAAAAAGCAUUUUUUUtt SEQ ID NO: 480 AAAAAAAGCAUUUUUUUUUtt SEQ ID NO: 481 AAAAAGCAUUUUUUUUUUAtt SEQ ID NO: 482 AAAGCAUUUUUUUUUUAUGtt SEQ ID NO: 483 AGCAUUUUUUUUUUAUGAUtt SEQ ID NO: 484 CGUUAUUUGUAAUUUAGUUtt SEQ ID NO: 485 UUUAGUUUGUAGCUCAUUAtt SEQ ID NO: 486 AAAAAUGUGCCUAGUUUUAtt SEQ ID NO: 487 AAAUGUGCCUAGUUUUAUAtt SEQ ID NO: 488 AUGUGCCUAGUUUUAUAAAtt

TABLE 6 Candidate siRNAs for ERBB3, SEQ ID NOs: 489-568 are based on NM_001005915 and SEQ ID NOs: 569-1120 are based on NM_001982. SEQ ID NO: 489 CGGCAGCGGAGGUUGCAAAtt SEQ ID NO: 490 GCGGCGACGGCAGCGGAGGtt SEQ ID NO: 491 CACCUGAACCGCUGGCGAAtt SEQ ID NO: 492 CAGCACCUGCAGAGCGUCGtt SEQ ID NO: 493 AGGACACACUGCCUGAGAGtt SEQ ID NO: 494 GCCGGUCACACUCAGGCCAtt SEQ ID NO: 495 GUACAGUGUCUGGUAUUGGtt SEQ ID NO: 496 GCUUGUACAGUGUCUGGUAtt SEQ ID NO: 497 CUCACACCUCUCGUAGAGCtt SEQ ID NO: 498 CGUGAGCACAAUCUCAAGGtt SEQ ID NO: 499 CAGGAAGGAGAGGUCGGCAtt SEQ ID NO: 500 CGAGGACAUAGCCUGUCACtt SEQ ID NO: 501 UGGUAGAGUAGAGAAUUCAtt SEQ ID NO: 502 GCAAUGGUAGAGUAGAGAAtt SEQ ID NO: 503 CCCUCGCACCACGCGGAGGtt SEQ ID NO: 504 CAUGACGAAGAUGGCAAACtt SEQ ID NO: 505 GCUGGAGUUGGUGUUAUAGtt SEQ ID NO: 506 AGCGUGGCUGGAGUUGGUGtt SEQ ID NO: 507 GCGCAGAGCGUGGCUGGAGtt SEQ ID NO: 508 CAUCAAGGAGGUACCAGUCtt SEQ ID NO: 509 GCACUUAGAGUGAGCAGUCtt SEQ ID NO: 510 GGCACCUUGGAAGAGGCACtt SEQ ID NO: 511 GGCCAAGGUGACAGGCACCtt SEQ ID NO: 512 CUUAGGGAGCAAUGGACCUtt SEQ ID NO: 513 ACUGGGGGCCCUCUAUUGCtt SEQ ID NO: 514 CCCUACUGGGGGCCCUCUAtt SEQ ID NO: 515 ACAAGGACACAGGGUUCCUtt SEQ ID NO: 516 GCCCCACAAGGACACAGGGtt SEQ ID NO: 517 UUUGAAAUUAGAAAAACGGtt SEQ ID NO: 518 GGUACACUGUACUUUGAAAtt SEQ ID NO: 519 GCCUCCGGUACACUGUACUtt SEQ ID NO: 520 GCCUCCCAAAAUGCUGGGAtt SEQ ID NO: 521 CUCAAGUGAUCUGCCCUCCtt SEQ ID NO: 522 GAGACAGGGUUUCGCCAUGtt SEQ ID NO: 523 UUUUUAGUAGAGACAGGGUtt SEQ ID NO: 524 AUUUUAUUUUUUUGUAUUUtt SEQ ID NO: 525 UUAUUUUAUUUUUUUGUAUtt SEQ ID NO: 526 UUUAUUUUAUUUUAUUUUUtt SEQ ID NO: 527 UUUUUAUUUUAUUUUAUUUtt SEQ ID NO: 528 AUUUUUUAUUUUAUUUUAUtt SEQ ID NO: 529 UUUGCAACCUCCGCUGCCGtt SEQ ID NO: 530 CCUCCGCUGCCGUCGCCGCtt SEQ ID NO: 531 UUCGCCAGCGGUUCAGGUGtt SEQ ID NO: 532 CGACGCUCUGCAGGUGCUGtt SEQ ID NO: 533 CUCUCAGGCAGUGUGUCCUtt SEQ ID NO: 534 UGGCCUGAGUGUGACCGGCtt SEQ ID NO: 535 CCAAUACCAGACACUGUACtt SEQ ID NO: 536 UACCAGACACUGUACAAGCtt SEQ ID NO: 537 GCUCUACGAGAGGUGUGAGtt SEQ ID NO: 538 CCUUGAGAUUGUGCUCACGtt SEQ ID NO: 539 UGCCGACCUCUCCUUCCUGtt SEQ ID NO: 540 GUGACAGGCUAUGUCCUCGtt SEQ ID NO: 541 UGAAUUCUCUACUCUACCAtt SEQ ID NO: 542 UUCUCUACUCUACCAUUGCtt SEQ ID NO: 543 CCUCCGCGUGGUGCGAGGGtt SEQ ID NO: 544 GUUUGCCAUCUUCGUCAUGtt SEQ ID NO: 545 CUAUAACACCAACUCCAGCtt SEQ ID NO: 546 CACCAACUCCAGCCACGCUtt SEQ ID NO: 547 CUCCAGCCACGCUCUGCGCtt SEQ ID NO: 548 GACUGGUACCUCCUUGAUGtt SEQ ID NO: 549 GACUGCUCACUCUAAGUGCtt SEQ ID NO: 550 GUGCCUCUUCCAAGGUGCCtt SEQ ID NO: 551 GGUGCCUGUCACCUUGGCCtt SEQ ID NO: 552 AGGUCCAUUGCUCCCUAAGtt SEQ ID NO: 553 GCAAUAGAGGGCCCCCAGUtt SEQ ID NO: 554 UAGAGGGCCCCCAGUAGGGtt SEQ ID NO: 555 AGGAACCCUGUGUCCUUGUtt SEQ ID NO: 556 CCCUGUGUCCUUGUGGGGCtt SEQ ID NO: 557 CCGUUUUUCUAAUUUCAAAtt SEQ ID NO: 558 UUUCAAAGUACAGUGUACCtt SEQ ID NO: 559 AGUACAGUGUACCGGAGGCtt SEQ ID NO: 560 UCCCAGCAUUUUGGGAGGCtt SEQ ID NO: 561 GGAGGGCAGAUCACUUGAGtt SEQ ID NO: 562 CAUGGCGAAACCCUGUCUCtt SEQ ID NO: 563 ACCCUGUCUCUACUAAAAAtt SEQ ID NO: 564 AAAUACAAAAAAAUAAAAUtt SEQ ID NO: 565 AUACAAAAAAAUAAAAUAAtt SEQ ID NO: 566 AAAAAUAAAAUAAAAUAAAtt SEQ ID NO: 567 AAAUAAAAUAAAAUAAAAAtt SEQ ID NO: 568 AUAAAAUAAAAUAAAAAAUtt SEQ ID NO: 569 CGGCAGCGGAGGUUGCAAAtt SEQ ID NO: 570 GCGGCGACGGCAGCGGAGGtt SEQ ID NO: 571 CACCUGAACCGCUGGCGAAtt SEQ ID NO: 572 CAGCACCUGCAGAGCGUCGtt SEQ ID NO: 573 AGGACACACUGCCUGAGAGtt SEQ ID NO: 574 GCCGGUCACACUCAGGCCAtt SEQ ID NO: 575 GUACAGUGUCUGGUAUUGGtt SEQ ID NO: 576 GCUUGUACAGUGUCUGGUAtt SEQ ID NO: 577 CUCACACCUCUCGUAGAGCtt SEQ ID NO: 578 CGUGAGCACAAUCUCAAGGtt SEQ ID NO: 579 CAGGAAGGAGAGGUCGGCAtt SEQ ID NO: 580 CGAGGACAUAGCCUGUCACtt SEQ ID NO: 581 UGGUAGAGUAGAGAAUUCAtt SEQ ID NO: 582 GCAAUGGUAGAGUAGAGAAtt SEQ ID NO: 583 CCCUCGCACCACGCGGAGGtt SEQ ID NO: 584 CAUGACGAAGAUGGCAAACtt SEQ ID NO: 585 GCUGGAGUUGGUGUUAUAGtt SEQ ID NO: 586 AGCGUGGCUGGAGUUGGUGtt SEQ ID NO: 587 GCGCAGAGCGUGGCUGGAGtt SEQ ID NO: 588 GUGACAAAGCUUAUCGUUCtt SEQ ID NO: 589 CAUGUGACAAAGCUUAUCGtt SEQ ID NO: 590 UGUGUCCAUGUGACAAAGCtt SEQ ID NO: 591 ACGAUGUCCCUCCAGUCAAtt SEQ ID NO: 592 ACAGCUUCUGCCAUUGUCCtt SEQ ID NO: 593 GGGGGGACAGCUUCUGCCAtt SEQ ID NO: 594 UCAUGACAGGGGGGACAGCtt SEQ ID NO: 595 AGGACCCCAGCAUCGCCCCtt SEQ ID NO: 596 UGGUCAAUGUCUGGCAGUCtt SEQ ID NO: 597 CUGAGGAGCACAGAUGGUCtt SEQ ID NO: 598 GGGCCCAAAGCAGUGACCAtt SEQ ID NO: 599 AUGGCAGCACUGGUUGGGGtt SEQ ID NO: 600 CUCAUCAUGGCAGCACUGGtt SEQ ID NO: 601 UACACAGGCUCCACUGUCAtt SEQ ID NO: 602 CAGCUGGAAAGUUAGCUUGtt SEQ ID NO: 603 UUCCAGCUGGAAAGUUAGCtt SEQ ID NO: 604 UUGGGUUCCAGCUGGAAAGtt SEQ ID NO: 605 ACUUGGUGUGGGGAUUGGGtt SEQ ID NO: 606 CUGAUACUUGGUGUGGGGAtt SEQ ID NO: 607 AACUCCUCCAUACUGAUACtt SEQ ID NO: 608 UGUUUGAUCCACCACAAAGtt SEQ ID NO: 609 AGGCCCUGACACAGGAUGUtt SEQ ID NO: 610 AUUUUUAUCUACUUCCAUCtt SEQ ID NO: 611 UGAGCCCAUUUUUAUCUACtt SEQ ID NO: 612 ACACAUCUUGAGCCCAUUUtt SEQ ID NO: 613 UCACACAUCUUGAGCCCAUtt SEQ ID NO: 614 CCCACAAGGCUCACACAUCtt SEQ ID NO: 615 GCCUGUUCCCUCACAGGCUtt SEQ ID NO: 616 AAGCGGCUCCCAGAGCCUGtt SEQ ID NO: 617 GUUCACAAAUCCAUCAAUGtt SEQ ID NO: 618 GCCCAGGAUCUUGGUGCAGtt SEQ ID NO: 619 GUCCAGGUUGCCCAGGAUCtt SEQ ID NO: 620 GGUGAUCAGAAAGUCCAGGtt SEQ ID NO: 621 CUUGUGCCAGGGGUCUCCAtt SEQ ID NO: 622 UGGGUCCAGGGCAGGGAUCtt SEQ ID NO: 623 UGUCCGGAAGACAUUGAGCtt SEQ ID NO: 624 CCGUACUGUCCGGAAGACAtt SEQ ID NO: 625 GGGCGGCCAGGACUGGAUGtt SEQ ID NO: 626 AUUGGAAAAAACACUGAAGtt SEQ ID NO: 627 GCCUCCAAUGGUUGUCAAAtt SEQ ID NO: 628 AGGCUUCUGCCUCCAAUGGtt SEQ ID NO: 629 AAGCCCCGGUUGUAGAGGCtt SEQ ID NO: 630 CAACAAUGAGAAGCCCCGGtt SEQ ID NO: 631 AGAUGUGACAUUCAAGUUCtt SEQ ID NO: 632 CAGAGAUGUGACAUUCAAGtt SEQ ID NO: 633 GAAGCCCAGAGAUGUGACAtt SEQ ID NO: 634 ACGCCCAGCACUAAUUUCCtt SEQ ID NO: 635 AGAUACGCCCAGCACUAAUtt SEQ ID NO: 636 CAGAGCUGCCUAUUGGCACtt SEQ ID NO: 637 GUGGUAGCAGAGCUGCCUAtt SEQ ID NO: 638 CCGAAGCACCUUGGUCCAGtt SEQ ID NO: 639 CGUAGGCCCCCGAAGCACCtt SEQ ID NO: 640 GCUUGAUGUCUAGUCGCUCtt SEQ ID NO: 641 UCUGCGCGGCCGAUUAUGCtt SEQ ID NO: 642 GCAGUCUCUGCGCGGCCGAtt SEQ ID NO: 643 GCACAGUGGGUCACACACUtt SEQ ID NO: 644 ACACCUCCUCGGCUAUAAUtt SEQ ID NO: 645 AGGCUCCCCAUUCAGAAAGtt SEQ ID NO: 646 AAAUUCUCGAGGCUCCCCAtt SEQ ID NO: 647 AUUCGGCCUCAUGGGCAAAtt SEQ ID NO: 648 CCGGGUGGCAGGAGAAGCAtt SEQ ID NO: 649 UGCCCUCCAUGGGUUGGCAtt SEQ ID NO: 650 UGGCAGUGCCCUCCAUGGGtt SEQ ID NO: 651 AGUAUCAGAGCCCGAGCCAtt SEQ ID NO: 652 CAUCUCGAAAAUGGGCACAtt SEQ ID NO: 653 GUACUUGUAGAUUGGGCCCtt SEQ ID NO: 654 ACAUCUGGGUACUUGUAGAtt SEQ ID NO: 655 AUUCUGAACAUCUGGGUACtt SEQ ID NO: 656 AUGGCAGGGCCGACAUUCAtt SEQ ID NO: 657 UCUCAUGGCAGGGCCGACAtt SEQ ID NO: 658 UUUACACCCCUGGGUGCAGtt SEQ ID NO: 659 GUCUUGAAGCUCUGGUCCUtt SEQ ID NO: 660 GUGUUUGUCCUAAACAGUCtt SEQ ID NO: 661 UGCCGAUCAGCACCAGUGUtt SEQ ID NO: 662 AGCCAUUGUCAGAUGGGUUtt SEQ ID NO: 663 AAAGCCAUUGUCAGAUGGGtt SEQ ID NO: 664 GCUAUCACUGUCAAAGCCAtt SEQ ID NO: 665 UCGCCUCAUAGCCCUUUUAtt SEQ ID NO: 666 GUAUCGCCUCAUAGCCCUUtt SEQ ID NO: 667 AAGUAUCGCCUCAUAGCCCtt SEQ ID NO: 668 GCUCUAUGCUCUCACCCCGtt SEQ ID NO: 669 GGCCAAGACUUUGUUAGCCtt SEQ ID NO: 670 GAUUCUGGCCAAGACUUUGtt SEQ ID NO: 671 GAAGAUUCUGGCCAAGACUtt SEQ ID NO: 672 AGCUCUGUCUCUUUGAAGAtt SEQ ID NO: 673 CUUCCUUAGCUCUGUCUCUtt SEQ ID NO: 674 CCAAGCACUUUAAGCUUCCtt SEQ ID NO: 675 CGAGCCAAGCACUUUAAGCtt SEQ ID NO: 676 GACACCCGAGCCAAGCACUtt SEQ ID NO: 677 CACACUCCUUUGUGCACAGtt SEQ ID NO: 678 CUCAGGGAUCCACACUCCUtt SEQ ID NO: 679 AGACUGGAAUCUUGAUUGAtt SEQ ID NO: 680 AUGCAGACUGGAAUCUUGAtt SEQ ID NO: 681 UUUAAUGCAGACUGGAAUCtt SEQ ID NO: 682 ACUCUUGUCCUCAAUGACUtt SEQ ID NO: 683 AAAACUCUGCCGUCCACUCtt SEQ ID NO: 684 GCAUAUGAUCUGUCACAGCtt SEQ ID NO: 685 GGGCAUAGUCCCAGCAGCCtt SEQ ID NO: 686 GAGAACCCAGAGGCAAAUAtt SEQ ID NO: 687 GCCCCAGUGCCCCCCGGUGtt SEQ ID NO: 688 GGCAAUUUGUACUCCCCAGtt SEQ ID NO: 689 AGUACAUUCCCUUGGCAAUtt SEQ ID NO: 690 CUCAAGGUAGUACAUUCCCtt SEQ ID NO: 691 UGUUCCUCAAGGUAGUACAtt SEQ ID NO: 692 UUCUAUGCACCAUACCAUGtt SEQ ID NO: 693 ACGUUUCGGGCAGCCAGGUtt SEQ ID NO: 694 GGUGACUUGAGUAGCACGUtt SEQ ID NO: 695 CUGAACCUGACUGGGUGACtt SEQ ID NO: 696 CUCACUGUAUAGCAGCUGCtt SEQ ID NO: 697 CAUCCACUUAAUUGGAGUCtt SEQ ID NO: 698 UCAAGGGCCAUCCACUUAAtt SEQ ID NO: 699 ACUCUCAAGGGCCAUCCACtt SEQ ID NO: 700 AUCACUCUGGUGUGUGUAUtt SEQ ID NO: 701 UCUCUAGCAGGUCUGGUACtt SEQ ID NO: 702 CUGUGCCAACCGCUCCCCCtt SEQ ID NO: 703 AUCACCAUGUAGACAUCAAtt SEQ ID NO: 704 CUCAUCAAUCAUCCAACACtt SEQ ID NO: 705 UUUAAAGGUUGGGCGAAUGtt SEQ ID NO: 706 UUGGCUAGUUCUUUAAAGGtt SEQ ID NO: 707 GAACUCAUUGGCUAGUUCUtt SEQ ID NO: 708 UGGUGAACUCAUUGGCUAGtt SEQ ID NO: 709 GGCCAUCCUGGUGAACUCAtt SEQ ID NO: 710 CCAGGCCCACUCUCUCUCUtt SEQ ID NO: 711 GGCUCUGGCCCAGGGGCUAtt SEQ ID NO: 712 ACUUCCUCUAGCUUCUUGUtt SEQ ID NO: 713 CUCUACUUCCUCUAGCUUCtt SEQ ID NO: 714 CAGCUCUACUUCCUCUAGCtt SEQ ID NO: 715 GUUCUGGCUCCAGCUCUACtt SEQ ID NO: 716 AGUCUAGGUCUAGGUCUAGtt SEQ ID NO: 717 CCAGGUUGUCCUCCUCUGCtt SEQ ID NO: 718 CAGUGUGGUGGUUGCCAGGtt SEQ ID NO: 719 GCGGAGCCCAGUGUGGUGGtt SEQ ID NO: 720 CCACGUGGCCGAUUAAGUGtt SEQ ID NO: 721 CUGGCUCCCACGUGGCCGAtt SEQ ID NO: 722 AUGUAUCCAGAUGAUGGACtt SEQ ID NO: 723 CUCCCCAAGAUUACCCUGGtt SEQ ID NO: 724 CUGGCAAGACUCCCCAAGAtt SEQ ID NO: 725 AGACUGGACGGGGGCACCGtt SEQ ID NO: 726 GCCAGGCAUCCCCGUGGCAtt SEQ ID NO: 727 AGCUCAGCCUCAGAGCCUGtt SEQ ID NO: 728 GCUCCUACACAUUGACACUtt SEQ ID NO: 729 CUGCUCCGGCUCCUACACAtt SEQ ID NO: 730 CAUAACCGUUGACAUCCUCtt SEQ ID NO: 731 AUCUGGCAUGACAUAACCGtt SEQ ID NO: 732 CCGGGAGGAGGGAGUACCUtt SEQ ID NO: 733 CCACUGAAGAAAGGGUGCCtt SEQ ID NO: 734 CCUCAUCUUCAUCUUCUUCtt SEQ ID NO: 735 ACUCCUCAUCUUCAUCUUCtt SEQ ID NO: 736 CAUACUCCUCAUCUUCAUCtt SEQ ID NO: 737 UGUAUUCAUACUCCUCAUCtt SEQ ID NO: 738 UUCUCCUCCGGUUCAUGUAtt SEQ ID NO: 739 ACUGUGCCUUCUCCUCCGGtt SEQ ID NO: 740 GGAUGAGGUGGACUGUGCCtt SEQ ID NO: 741 CCCAGCUCCUCAAGGGAACtt SEQ ID NO: 742 UCAUAGUCUUCAUCUGGAGtt SEQ ID NO: 743 GAUUCAUAUAUUCAUAGUCtt SEQ ID NO: 744 CUCGUUGCCGAUUCAUAUAtt SEQ ID NO: 745 ACCUCCAUCUCGUUGCCGAtt SEQ ID NO: 746 CAGGACCACCUCCAUCUCGtt SEQ ID NO: 747 CUCUCAUCUCUUCAUACCCtt SEQ ID NO: 748 CCUGAAAAGCUCUCAUCUCtt SEQ ID NO: 749 UCUAAGCUACGUAGAGUUUtt SEQ ID NO: 750 CCUCUAAGCUACGUAGAGUtt SEQ ID NO: 751 GCUAUGCCAGUAAUCAGGGtt SEQ ID NO: 752 CGUUCUCUGGGCAUUAGCCtt SEQ ID NO: 753 GAGUUACGUUCUCUGGGCAtt SEQ ID NO: 754 ACAGGGAGCAGGAGUUACGtt SEQ ID NO: 755 GUGCCACAGGGAGCAGGAGtt SEQ ID NO: 756 CUAAAGGCACUAGCUGCCAtt SEQ ID NO: 757 CUCCAAAGAUUGAAUGGAAtt SEQ ID NO: 758 GUUUAAAAGCCUCCAAAGAtt SEQ ID NO: 759 GAAUUUUGUGUCAAAAUGUtt SEQ ID NO: 760 GCUACAUACCAUAAGAAUUtt SEQ ID NO: 761 UGGCUACAUACCAUAAGAAtt SEQ ID NO: 762 AGGAAAACCUUUCCUGGGGtt SEQ ID NO: 763 CACAAAAUAAGGAAAACCUtt SEQ ID NO: 764 GGGAUAUGGAGAGUAAUCCtt SEQ ID NO: 765 GGCACACAUAAGAGCCUAGtt SEQ ID NO: 766 UUUCCUCCCUUUCCUCUUCtt SEQ ID NO: 767 AGGUUUCCUCCCUUUCCUCtt SEQ ID NO: 768 UCUGCUAGGUUUCCUCCCUtt SEQ ID NO: 769 ACACUUUCCUCUGCUAGGUtt SEQ ID NO: 770 CAUAAACCAAAAUUACACUtt SEQ ID NO: 771 UAAGAGUCAUAAACCAAAAtt SEQ ID NO: 772 CUUCUGUCUUUCUAGGGGGtt SEQ ID NO: 773 AGAUUUUAAGCUUCUGUCUtt SEQ ID NO: 774 UUCUUCACAGAUUUUAAGCtt SEQ ID NO: 775 ACCUCUUUCUUCACAGAUUtt SEQ ID NO: 776 UAACCUCUUUCUUCACAGAtt SEQ ID NO: 777 UCUACUCCUAACCUCUUUCtt SEQ ID NO: 778 AUAUCUACUCCUAACCUCUtt SEQ ID NO: 779 CUCAUAGUUAAGUGCUGAAtt SEQ ID NO: 780 UAUGAUGCCUGGCUCAUAGtt SEQ ID NO: 781 GAGAUAAUGUAGGUGAAGUtt SEQ ID NO: 782 UGUAUGUCACAGAAUUGUUtt SEQ ID NO: 783 UAUGUAUGUCACAGAAUUGtt SEQ ID NO: 784 UAAUAUGUAUGUCACAGAAtt SEQ ID NO: 785 CACCAUGCCCGACUUCCCUtt SEQ ID NO: 786 AUGAGCCACCAUGCCCGACtt SEQ ID NO: 787 GCCUCCCAAAGUGCUGAGAtt SEQ ID NO: 788 UCCUUGCCUCAGGUAAUCCtt SEQ ID NO: 789 UAAGCUGGUCUCAAACUCCtt SEQ ID NO: 790 AGAUGGGGGUCUUACUAUGtt SEQ ID NO: 791 UUUUAAAGAGAUGGGGGUCtt SEQ ID NO: 792 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 793 GUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 794 AAGUUUUUUUUUUUUUUUUtt SEQ ID NO: 795 UAAAGUUUUUUUUUUUUUUtt SEQ ID NO: 796 UCUAAAGUUUUUUUUUUUUtt SEQ ID NO: 797 GUUCUAAAGUUUUUUUUUUtt SEQ ID NO: 798 CAGUUCUAAAGUUUUUUUUtt SEQ ID NO: 799 CCCAGUUCUAAAGUUUUUUtt SEQ ID NO: 800 CACCCAGUUCUAAAGUUUUtt SEQ ID NO: 801 UGCACCCAGUUCUAAAGUUtt SEQ ID NO: 802 ACUGCACCCAGUUCUAAAGtt SEQ ID NO: 803 CAUGAGCCACUGCACCCAGtt SEQ ID NO: 804 CCCAAAGUGCUGGCUGGGAtt SEQ ID NO: 805 AUUCUGGGCUCAAGUGAUCtt SEQ ID NO: 806 UCCAUAGGCUUAUCUCUAAtt SEQ ID NO: 807 UUGCUAUGUUUCCAUAGGCtt SEQ ID NO: 808 AGACAGUGUCUUGCUAUGUtt SEQ ID NO: 809 CCCCUGUAGAGACAGUGUCtt SEQ ID NO: 810 CUCAGUUUCUUUUUUUUUUtt SEQ ID NO: 811 GGCUCAGUUUCUUUUUUUUtt SEQ ID NO: 812 AAGGCUCAGUUUCUUUUUUtt SEQ ID NO: 813 UUAAGGCUCAGUUUCUUUUtt SEQ ID NO: 814 CUUUAAGGCUCAGUUUCUUtt SEQ ID NO: 815 CUCUUUAAGGCUCAGUUUCtt SEQ ID NO: 816 CAUCUCUUUAAGGCUCAGUtt SEQ ID NO: 817 CUUAAUUUAUUUCAUCUCUtt SEQ ID NO: 818 GAUCUACUGCUUAAUUUAUtt SEQ ID NO: 819 CCUGGAUCUACUGCUUAAUtt SEQ ID NO: 820 UGCAUCCUGGAUCUACUGCtt SEQ ID NO: 821 CACAGGAAUUGGGAGGAUUtt SEQ ID NO: 822 UGCACAGGAAUUGGGAGGAtt SEQ ID NO: 823 AAGAGCACAUGCACAGGAAtt SEQ ID NO: 824 AUCAGUUUUUCUUGGCACCtt SEQ ID NO: 825 UAACUUAAAUCAGUUUUUCtt SEQ ID NO: 826 CUGUAACUUAAAUCAGUUUtt SEQ ID NO: 827 GGCUGUAACUUAAAUCAGUtt SEQ ID NO: 828 CUUAAACAAGGGCUGUAACtt SEQ ID NO: 829 AAACAAGAAACAGUGCCCCtt SEQ ID NO: 830 CUGUUGGGGUUAGACUUGAtt SEQ ID NO: 831 GUGGCUGUUGGGGUUAGACtt SEQ ID NO: 832 GAGGAUGUGGCUGUUGGGGtt SEQ ID NO: 833 GUAUAGGAGGAUGUGGCUGtt SEQ ID NO: 834 UGACUACCCCCACCACCACtt SEQ ID NO: 835 GAUGUCCAGUUAUUUUUCCtt SEQ ID NO: 836 CAAAGAUGUCCAGUUAUUUtt SEQ ID NO: 837 CACAAAGAUGUCCAGUUAUtt SEQ ID NO: 838 UUUACACAAAGAUGUCCAGtt SEQ ID NO: 839 GGCACAUGUGGAUUAUGGUtt SEQ ID NO: 840 CAUUUACGGCACAUGUGGAtt SEQ ID NO: 841 GAUAAGGAGUGAAGAUCAUtt SEQ ID NO: 842 CUUGGGGAUCCUUGUGAAUtt SEQ ID NO: 843 AAGUGGAUCUUGGGGAUCCtt SEQ ID NO: 844 UGGCUUCUAAAAGUGGAUCtt SEQ ID NO: 845 UUUGCAACCUCCGCUGCCGtt SEQ ID NO: 846 CCUCCGCUGCCGUCGCCGCtt SEQ ID NO: 847 UUCGCCAGCGGUUCAGGUGtt SEQ ID NO: 848 CGACGCUCUGCAGGUGCUGtt SEQ ID NO: 849 CUCUCAGGCAGUGUGUCCUtt SEQ ID NO: 850 UGGCCUGAGUGUGACCGGCtt SEQ ID NO: 851 CCAAUACCAGACACUGUACtt SEQ ID NO: 852 UACCAGACACUGUACAAGCtt SEQ ID NO: 853 GCUCUACGAGAGGUGUGAGtt SEQ ID NO: 854 CCUUGAGAUUGUGCUCACGtt SEQ ID NO: 855 UGCCGACCUCUCCUUCCUGtt SEQ ID NO: 856 GUGACAGGCUAUGUCCUCGtt SEQ ID NO: 857 UGAAUUCUCUACUCUACCAtt SEQ ID NO: 858 UUCUCUACUCUACCAUUGCtt SEQ ID NO: 859 CCUCCGCGUGGUGCGAGGGtt SEQ ID NO: 860 GUUUGCCAUCUUCGUCAUGtt SEQ ID NO: 861 CUAUAACACCAACUCCAGCtt SEQ ID NO: 862 CACCAACUCCAGCCACGCUtt SEQ ID NO: 863 CUCCAGCCACGCUCUGCGCtt SEQ ID NO: 864 GAACGAUAAGCUUUGUCACtt SEQ ID NO: 865 CGAUAAGCUUUGUCACAUGtt SEQ ID NO: 866 GCUUUGUCACAUGGACACAtt SEQ ID NO: 867 UUGACUGGAGGGACAUCGUtt SEQ ID NO: 868 GGACAAUGGCAGAAGCUGUtt SEQ ID NO: 869 UGGCAGAAGCUGUCCCCCCtt SEQ ID NO: 870 GCUGUCCCCCCUGUCAUGAtt SEQ ID NO: 871 GGGGCGAUGCUGGGGUCCUtt SEQ ID NO: 872 GACUGCCAGACAUUGACCAtt SEQ ID NO: 873 GACCAUCUGUGCUCCUCAGtt SEQ ID NO: 874 UGGUCACUGCUUUGGGCCCtt SEQ ID NO: 875 CCCCAACCAGUGCUGCCAUtt SEQ ID NO: 876 CCAGUGCUGCCAUGAUGAGtt SEQ ID NO: 877 UGACAGUGGAGCCUGUGUAtt SEQ ID NO: 878 CAAGCUAACUUUCCAGCUGtt SEQ ID NO: 879 GCUAACUUUCCAGCUGGAAtt SEQ ID NO: 880 CUUUCCAGCUGGAACCCAAtt SEQ ID NO: 881 CCCAAUCCCCACACCAAGUtt SEQ ID NO: 882 UCCCCACACCAAGUAUCAGtt SEQ ID NO: 883 GUAUCAGUAUGGAGGAGUUtt SEQ ID NO: 884 CUUUGUGGUGGAUCAAACAtt SEQ ID NO: 885 ACAUCCUGUGUCAGGGCCUtt SEQ ID NO: 886 GAUGGAAGUAGAUAAAAAUtt SEQ ID NO: 887 GUAGAUAAAAAUGGGCUCAtt SEQ ID NO: 888 AAAUGGGCUCAAGAUGUGUtt SEQ ID NO: 889 AUGGGCUCAAGAUGUGUGAtt SEQ ID NO: 890 GAUGUGUGAGCCUUGUGGGtt SEQ ID NO: 891 AGCCUGUGAGGGAACAGGCtt SEQ ID NO: 892 CAGGCUCUGGGAGCCGCUUtt SEQ ID NO: 893 CAUUGAUGGAUUUGUGAACtt SEQ ID NO: 894 CUGCACCAAGAUCCUGGGCtt SEQ ID NO: 895 GAUCCUGGGCAACCUGGACtt SEQ ID NO: 896 CCUGGACUUUCUGAUCACCtt SEQ ID NO: 897 UGGAGACCCCUGGCACAAGtt SEQ ID NO: 898 GAUCCCUGCCCUGGACCCAtt SEQ ID NO: 899 GCUCAAUGUCUUCCGGACAtt SEQ ID NO: 900 UGUCUUCCGGACAGUACGGtt SEQ ID NO: 901 CAUCCAGUCCUGGCCGCCCtt SEQ ID NO: 902 CUUCAGUGUUUUUUCCAAUtt SEQ ID NO: 903 UUUGACAACCAUUGGAGGCtt SEQ ID NO: 904 CCAUUGGAGGCAGAAGCCUtt SEQ ID NO: 905 GCCUCUACAACCGGGGCUUtt SEQ ID NO: 906 CCGGGGCUUCUCAUUGUUGtt SEQ ID NO: 907 GAACUUGAAUGUCACAUCUtt SEQ ID NO: 908 CUUGAAUGUCACAUCUCUGtt SEQ ID NO: 909 UGUCACAUCUCUGGGCUUCtt SEQ ID NO: 910 GGAAAUUAGUGCUGGGCGUtt SEQ ID NO: 911 AUUAGUGCUGGGCGUAUCUtt SEQ ID NO: 912 GUGCCAAUAGGCAGCUCUGtt SEQ ID NO: 913 UAGGCAGCUCUGCUACCACtt SEQ ID NO: 914 CUGGACCAAGGUGCUUCGGtt SEQ ID NO: 915 GGUGCUUCGGGGGCCUACGtt SEQ ID NO: 916 GAGCGACUAGACAUCAAGCtt SEQ ID NO: 917 GCAUAAUCGGCCGCGCAGAtt SEQ ID NO: 918 UCGGCCGCGCAGAGACUGCtt SEQ ID NO: 919 AGUGUGUGACCCACUGUGCtt SEQ ID NO: 920 AUUAUAGCCGAGGAGGUGUtt SEQ ID NO: 921 CUUUCUGAAUGGGGAGCCUtt SEQ ID NO: 922 UGGGGAGCCUCGAGAAUUUtt SEQ ID NO: 923 UUUGCCCAUGAGGCCGAAUtt SEQ ID NO: 924 UGCUUCUCCUGCCACCCGGtt SEQ ID NO: 925 UGCCAACCCAUGGAGGGCAtt SEQ ID NO: 926 CCCAUGGAGGGCACUGCCAtt SEQ ID NO: 927 UGGCUCGGGCUCUGAUACUtt SEQ ID NO: 928 UGUGCCCAUUUUCGAGAUGtt SEQ ID NO: 929 GGGCCCAAUCUACAAGUACtt SEQ ID NO: 930 UCUACAAGUACCCAGAUGUtt SEQ ID NO: 931 GUACCCAGAUGUUCAGAAUtt SEQ ID NO: 932 UGAAUGUCGGCCCUGCCAUtt SEQ ID NO: 933 UGUCGGCCCUGCCAUGAGAtt SEQ ID NO: 934 CUGCACCCAGGGGUGUAAAtt SEQ ID NO: 935 AGGACCAGAGCUUCAAGACtt SEQ ID NO: 936 GACUGUUUAGGACAAACACtt SEQ ID NO: 937 ACACUGGUGCUGAUCGGCAtt SEQ ID NO: 938 AACCCAUCUGACAAUGGCUtt SEQ ID NO: 939 CCCAUCUGACAAUGGCUUUtt SEQ ID NO: 940 UGGCUUUGACAGUGAUAGCtt SEQ ID NO: 941 UAAAAGGGCUAUGAGGCGAtt SEQ ID NO: 942 AAGGGCUAUGAGGCGAUACtt SEQ ID NO: 943 GGGCUAUGAGGCGAUACUUtt SEQ ID NO: 944 CGGGGUGAGAGCAUAGAGCtt SEQ ID NO: 945 GGCUAACAAAGUCUUGGCCtt SEQ ID NO: 946 CAAAGUCUUGGCCAGAAUCtt SEQ ID NO: 947 AGUCUUGGCCAGAAUCUUCtt SEQ ID NO: 948 UCUUCAAAGAGACAGAGCUtt SEQ ID NO: 949 AGAGACAGAGCUAAGGAAGtt SEQ ID NO: 950 GGAAGCUUAAAGUGCUUGGtt SEQ ID NO: 951 GCUUAAAGUGCUUGGCUCGtt SEQ ID NO: 952 AGUGCUUGGCUCGGGUGUCtt SEQ ID NO: 953 CUGUGCACAAAGGAGUGUGtt SEQ ID NO: 954 AGGAGUGUGGAUCCCUGAGtt SEQ ID NO: 955 UCAAUCAAGAUUCCAGUCUtt SEQ ID NO: 956 UCAAGAUUCCAGUCUGCAUtt SEQ ID NO: 957 GAUUCCAGUCUGCAUUAAAtt SEQ ID NO: 958 AGUCAUUGAGGACAAGAGUtt SEQ ID NO: 959 GAGUGGACGGCAGAGUUUUtt SEQ ID NO: 960 GCUGUGACAGAUCAUAUGCtt SEQ ID NO: 961 GGCUGCUGGGACUAUGCCCtt SEQ ID NO: 962 UAUUUGCCUCUGGGUUCUCtt SEQ ID NO: 963 CACCGGGGGGCACUGGGGCtt SEQ ID NO: 964 CUGGGGAGUACAAAUUGCCtt SEQ ID NO: 965 AUUGCCAAGGGAAUGUACUtt SEQ ID NO: 966 GGGAAUGUACUACCUUGAGtt SEQ ID NO: 967 UGUACUACCUUGAGGAACAtt SEQ ID NO: 968 CAUGGUAUGGUGCAUAGAAtt SEQ ID NO: 969 ACCUGGCUGCCCGAAACGUtt SEQ ID NO: 970 ACGUGCUACUCAAGUCACCtt SEQ ID NO: 971 GUCACCCAGUCAGGUUCAGtt SEQ ID NO: 972 GCAGCUGCUAUACAGUGAGtt SEQ ID NO: 973 GACUCCAAUUAAGUGGAUGtt SEQ ID NO: 974 UUAAGUGGAUGGCCCUUGAtt SEQ ID NO: 975 GUGGAUGGCCCUUGAGAGUtt SEQ ID NO: 976 AUACACACACCAGAGUGAUtt SEQ ID NO: 977 GUACCAGACCUGCUAGAGAtt SEQ ID NO: 978 GGGGGAGCGGUUGGCACAGtt SEQ ID NO: 979 UUGAUGUCUACAUGGUGAUtt SEQ ID NO: 980 GUGUUGGAUGAUUGAUGAGtt SEQ ID NO: 981 CAUUCGCCCAACCUUUAAAtt SEQ ID NO: 982 CCUUUAAAGAACUAGCCAAtt SEQ ID NO: 983 AGAACUAGCCAAUGAGUUCtt SEQ ID NO: 984 CUAGCCAAUGAGUUCACCAtt SEQ ID NO: 985 UGAGUUCACCAGGAUGGCCtt SEQ ID NO: 986 AGAGAGAGAGUGGGCCUGGtt SEQ ID NO: 987 UAGCCCCUGGGCCAGAGCCtt SEQ ID NO: 988 ACAAGAAGCUAGAGGAAGUtt SEQ ID NO: 989 GAAGCUAGAGGAAGUAGAGtt SEQ ID NO: 990 GCUAGAGGAAGUAGAGCUGtt SEQ ID NO: 991 GUAGAGCUGGAGCCAGAACtt SEQ ID NO: 992 CUAGACCUAGACCUAGACUtt SEQ ID NO: 993 GCAGAGGAGGACAACCUGGtt SEQ ID NO: 994 CCUGGCAACCACCACACUGtt SEQ ID NO: 995 CCACCACACUGGGCUCCGCtt SEQ ID NO: 996 CACUUAAUCGGCCACGUGGtt SEQ ID NO: 997 UCGGCCACGUGGGAGCCAGtt SEQ ID NO: 998 GUCCAUCAUCUGGAUACAUtt SEQ ID NO: 999 CCAGGGUAAUCUUGGGGAGtt SEQ ID NO: 1000 UCUUGGGGAGUCUUGCCAGtt SEQ ID NO: 1001 CGGUGCCCCCGUCCAGUCUtt SEQ ID NO: 1002 UGCCACGGGGAUGCCUGGCtt SEQ ID NO: 1003 CAGGCUCUGAGGCUGAGCUtt SEQ ID NO: 1004 AGUGUCAAUGUGUAGGAGCtt SEQ ID NO: 1005 UGUGUAGGAGCCGGAGCAGtt SEQ ID NO: 1006 GAGGAUGUCAACGGUUAUGtt SEQ ID NO: 1007 CGGUUAUGUCAUGCCAGAUtt SEQ ID NO: 1008 AGGUACUCCCUCCUCCCGGtt SEQ ID NO: 1009 GGCACCCUUUCUUCAGUGGtt SEQ ID NO: 1010 GAAGAAGAUGAAGAUGAGGtt SEQ ID NO: 1011 GAAGAUGAAGAUGAGGAGUtt SEQ ID NO: 1012 GAUGAAGAUGAGGAGUAUGtt SEQ ID NO: 1013 GAUGAGGAGUAUGAAUACAtt SEQ ID NO: 1014 UACAUGAACCGGAGGAGAAtt SEQ ID NO: 1015 CCGGAGGAGAAGGCACAGUtt SEQ ID NO: 1016 GGCACAGUCCACCUCAUCCtt SEQ ID NO: 1017 GUUCCCUUGAGGAGCUGGGtt SEQ ID NO: 1018 CUCCAGAUGAAGACUAUGAtt SEQ ID NO: 1019 GACUAUGAAUAUAUGAAUCtt SEQ ID NO: 1020 UAUAUGAAUCGGCAACGAGtt SEQ ID NO: 1021 UCGGCAACGAGAUGGAGGUtt SEQ ID NO: 1022 CGAGAUGGAGGUGGUCCUGtt SEQ ID NO: 1023 GGGUAUGAAGAGAUGAGAGtt SEQ ID NO: 1024 GAGAUGAGAGCUUUUCAGGtt SEQ ID NO: 1025 AAACUCUACGUAGCUUAGAtt SEQ ID NO: 1026 ACUCUACGUAGCUUAGAGGtt SEQ ID NO: 1027 CCCUGAUUACUGGCAUAGCtt SEQ ID NO: 1028 GGCUAAUGCCCAGAGAACGtt SEQ ID NO: 1029 UGCCCAGAGAACGUAACUCtt SEQ ID NO: 1030 CGUAACUCCUGCUCCCUGUtt SEQ ID NO: 1031 CUCCUGCUCCCUGUGGCACtt SEQ ID NO: 1032 UGGCAGCUAGUGCCUUUAGtt SEQ ID NO: 1033 UUCCAUUCAAUCUUUGGAGtt SEQ ID NO: 1034 UCUUUGGAGGCUUUUAAACtt SEQ ID NO: 1035 ACAUUUUGACACAAAAUUCtt SEQ ID NO: 1036 AAUUCUUAUGGUAUGUAGCtt SEQ ID NO: 1037 UUCUUAUGGUAUGUAGCCAtt SEQ ID NO: 1038 CCCCAGGAAAGGUUUUCCUtt SEQ ID NO: 1039 AGGUUUUCCUUAUUUUGUGtt SEQ ID NO: 1040 GGAUUACUCUCCAUAUCCCtt SEQ ID NO: 1041 CUAGGCUCUUAUGUGUGCCtt SEQ ID NO: 1042 GAAGAGGAAAGGGAGGAAAtt SEQ ID NO: 1043 GAGGAAAGGGAGGAAACCUtt SEQ ID NO: 1044 AGGGAGGAAACCUAGCAGAtt SEQ ID NO: 1045 ACCUAGCAGAGGAAAGUGUtt SEQ ID NO: 1046 AGUGUAAUUUUGGUUUAUGtt SEQ ID NO: 1047 UUUUGGUUUAUGACUCUUAtt SEQ ID NO: 1048 CCCCCUAGAAAGACAGAAGtt SEQ ID NO: 1049 AGACAGAAGCUUAAAAUCUtt SEQ ID NO: 1050 GCUUAAAAUCUGUGAAGAAtt SEQ ID NO: 1051 AAUCUGUGAAGAAAGAGGUtt SEQ ID NO: 1052 UCUGUGAAGAAAGAGGUUAtt SEQ ID NO: 1053 GAAAGAGGUUAGGAGUAGAtt SEQ ID NO: 1054 AGAGGUUAGGAGUAGAUAUtt SEQ ID NO: 1055 UUCAGCACUUAACUAUGAGtt SEQ ID NO: 1056 CUAUGAGCCAGGCAUCAUAtt SEQ ID NO: 1057 ACUUCACCUACAUUAUCUCtt SEQ ID NO: 1058 AACAAUUCUGUGACAUACAtt SEQ ID NO: 1059 CAAUUCUGUGACAUACAUAtt SEQ ID NO: 1060 UUCUGUGACAUACAUAUUAtt SEQ ID NO: 1061 AGGGAAGUCGGGCAUGGUGtt SEQ ID NO: 1062 GUCGGGCAUGGUGGCUCAUtt SEQ ID NO: 1063 UCUCAGCACUUUGGGAGGCtt SEQ ID NO: 1064 GGAUUACCUGAGGCAAGGAtt SEQ ID NO: 1065 GGAGUUUGAGACCAGCUUAtt SEQ ID NO: 1066 CAUAGUAAGACCCCCAUCUtt SEQ ID NO: 1067 GACCCCCAUCUCUUUAAAAtt SEQ ID NO: 1068 AAAAAAAAAAAAAAAAAAAtt SEQ ID NO: 1069 AAAAAAAAAAAAAAAAAACtt SEQ ID NO: 1070 AAAAAAAAAAAAAAAACUUtt SEQ ID NO: 1071 AAAAAAAAAAAAAACUUUAtt SEQ ID NO: 1072 AAAAAAAAAAAACUUUAGAtt SEQ ID NO: 1073 AAAAAAAAAACUUUAGAACtt SEQ ID NO: 1074 AAAAAAAACUUUAGAACUGtt SEQ ID NO: 1075 AAAAAACUUUAGAACUGGGtt SEQ ID NO: 1076 AAAACUUUAGAACUGGGUGtt SEQ ID NO: 1077 AACUUUAGAACUGGGUGCAtt SEQ ID NO: 1078 CUUUAGAACUGGGUGCAGUtt SEQ ID NO: 1079 CUGGGUGCAGUGGCUCAUGtt SEQ ID NO: 1080 UCCCAGCCAGCACUUUGGGtt SEQ ID NO: 1081 GAUCACUUGAGCCCAGAAUtt SEQ ID NO: 1082 UUAGAGAUAAGCCUAUGGAtt SEQ ID NO: 1083 GCCUAUGGAAACAUAGCAAtt SEQ ID NO: 1084 ACAUAGCAAGACACUGUCUtt SEQ ID NO: 1085 GACACUGUCUCUACAGGGGtt SEQ ID NO: 1086 AAAAAAAAAAGAAACUGAGtt SEQ ID NO: 1087 AAAAAAAAGAAACUGAGCCtt SEQ ID NO: 1088 AAAAAAGAAACUGAGCCUUtt SEQ ID NO: 1089 AAAAGAAACUGAGCCUUAAtt SEQ ID NO: 1090 AAGAAACUGAGCCUUAAAGtt SEQ ID NO: 1091 GAAACUGAGCCUUAAAGAGtt SEQ ID NO: 1092 ACUGAGCCUUAAAGAGAUGtt SEQ ID NO: 1093 AGAGAUGAAAUAAAUUAAGtt SEQ ID NO: 1094 AUAAAUUAAGCAGUAGAUCtt SEQ ID NO: 1095 AUUAAGCAGUAGAUCCAGGtt SEQ ID NO: 1096 GCAGUAGAUCCAGGAUGCAtt SEQ ID NO: 1097 AAUCCUCCCAAUUCCUGUGtt SEQ ID NO: 1098 UCCUCCCAAUUCCUGUGCAtt SEQ ID NO: 1099 UUCCUGUGCAUGUGCUCUUtt SEQ ID NO: 1100 GGUGCCAAGAAAAACUGAUtt SEQ ID NO: 1101 GAAAAACUGAUUUAAGUUAtt SEQ ID NO: 1102 AAACUGAUUUAAGUUACAGtt SEQ ID NO: 1103 ACUGAUUUAAGUUACAGCCtt SEQ ID NO: 1104 GUUACAGCCCUUGUUUAAGtt SEQ ID NO: 1105 GGGGCACUGUUUCUUGUUUtt SEQ ID NO: 1106 UCAAGUCUAACCCCAACAGtt SEQ ID NO: 1107 GUCUAACCCCAACAGCCACtt SEQ ID NO: 1108 CCCCAACAGCCACAUCCUCtt SEQ ID NO: 1109 CAGCCACAUCCUCCUAUACtt SEQ ID NO: 1110 GUGGUGGUGGGGGUAGUCAtt SEQ ID NO: 1111 GGAAAAAUAACUGGACAUCtt SEQ ID NO: 1112 AAAUAACUGGACAUCUUUGtt SEQ ID NO: 1113 AUAACUGGACAUCUUUGUGtt SEQ ID NO: 1114 CUGGACAUCUUUGUGUAAAtt SEQ ID NO: 1115 ACCAUAAUCCACAUGUGCCtt SEQ ID NO: 1116 UCCACAUGUGCCGUAAAUGtt SEQ ID NO: 1117 AUGAUCUUCACUCCUUAUCtt SEQ ID NO: 1118 AUUCACAAGGAUCCCCAAGtt SEQ ID NO: 1119 GGAUCCCCAAGAUCCACUUtt SEQ ID NO: 1120 GAUCCACUUUUAGAAGCCAtt

TABLE 7 Candidate siRNAs for IKZF4, SEQ ID NOs: 1121-1592 are based on NM_022465. SEQ ID NO: 1121 GGCCCAGGACACGGACAGCtt SEQ ID NO: 1122 GAGGGAAAGGCAGAUGCUGtt SEQ ID NO: 1123 CUAGGCUACAGCAUCCCUUtt SEQ ID NO: 1124 UGCUAGGCUACAGCAUCCCtt SEQ ID NO: 1125 AGAGCACGCUUGGAUGUGCtt SEQ ID NO: 1126 AGGAGAGGGGAGAGCACGCtt SEQ ID NO: 1127 AGCCCAGGGUGUAUGUGUGtt SEQ ID NO: 1128 UGAGGGGAACCGCCGUCAUtt SEQ ID NO: 1129 ACCUUCCAGGAAGCGUGGAtt SEQ ID NO: 1130 GUGAGCCCAGCCACUCACCtt SEQ ID NO: 1131 UGCGAACGCGGCCGCCGCCtt SEQ ID NO: 1132 UCUCCAGAUUAUCCUUCCCtt SEQ ID NO: 1133 AUCCCUCUCCAGAUUAUCCtt SEQ ID NO: 1134 UGAGGGAUCCCUCUCCAGAtt SEQ ID NO: 1135 UUAUAAAAUGGUUGGAGUCtt SEQ ID NO: 1136 AGAUUCCAUUAUAAAAUGGtt SEQ ID NO: 1137 UCACAAAAUAAAGAUUCCAtt SEQ ID NO: 1138 UACUUUCACAAAAUAAAGAtt SEQ ID NO: 1139 GAGAUGAGUCCCCGCUACUtt SEQ ID NO: 1140 UGGGGCCCCGAGGAACUCCtt SEQ ID NO: 1141 AGGAGAAGAGUGCUGGCUGtt SEQ ID NO: 1142 CAUCUCCACCUUGAUGGAGtt SEQ ID NO: 1143 AUCGCUGUACAUCUCCACCtt SEQ ID NO: 1144 UCUGGCCCCAGCAGUCUGCtt SEQ ID NO: 1145 CAAUCACGCUGUCGUCCUUtt SEQ ID NO: 1146 CACAAUCACGCUGUCGUCCtt SEQ ID NO: 1147 GGGGCUCAGACAAUGAAUCtt SEQ ID NO: 1148 GUCACACUUGAGCUUGCCAtt SEQ ID NO: 1149 GCAGACGUCACACUUGAGCtt SEQ ID NO: 1150 CAUGCCGCAGACGUCACACtt SEQ ID NO: 1151 CUUGUGCACCAUGAGCACGtt SEQ ID NO: 1152 UUCACCAGUGUGACUGCGCtt SEQ ID NO: 1153 GGUUGCAAUGGAAGGGCCUtt SEQ ID NO: 1154 GAAGGAGGCACCACACUGGtt SEQ ID NO: 1155 GUGGCGCAGCAGGUUCCCCtt SEQ ID NO: 1156 CUUGAUGUGGCGCAGCAGGtt SEQ ID NO: 1157 CUUCUCCCCAGAGUGCAGCtt SEQ ID NO: 1158 GAAGGGACAUUUAAAGGGCtt SEQ ID NO: 1159 AUAGUUGCAGAAGGGACAUtt SEQ ID NO: 1160 ACGCCGGCGGCAGGCAUAGtt SEQ ID NO: 1161 GUAGUUACACUUGUAGGGCtt SEQ ID NO: 1162 CCGGCCACAGUAGUUACACtt SEQ ID NO: 1163 GUAGCUCCGGCCACAGUAGtt SEQ ID NO: 1164 CUCCAGGGUACUCUGCUGUtt SEQ ID NO: 1165 GUAGUUAUGGCACCGCUCCtt SEQ ID NO: 1166 GCUGAGACUCUGUAGGUAGtt SEQ ID NO: 1167 GGCCAGCCAAAGCUUGGGCtt SEQ ID NO: 1168 CUGGUUGGCCAGCCAAAGCtt SEQ ID NO: 1169 CACGUAUUUCGUCACCUGGtt SEQ ID NO: 1170 CCAUCUCCAGGUCACGUAUtt SEQ ID NO: 1171 GCCAGACGAUCGAUGAAAGtt SEQ ID NO: 1172 CUUGCGUUUGGUGAGGCUAtt SEQ ID NO: 1173 GGGUGUGGAACGCUUGCGUtt SEQ ID NO: 1174 CUUCUGGGGUGUGGAACGCtt SEQ ID NO: 1175 CUGCUUUUCGCCUACAAACtt SEQ ID NO: 1176 GGCUGAAGCGCAUCUGCUUtt SEQ ID NO: 1177 GAGGCUGAAGCGCAUCUGCtt SEQ ID NO: 1178 CUUUUCAUAGCCACCCGAGtt SEQ ID NO: 1179 CCACCAACUCCACAUCCUUtt SEQ ID NO: 1180 UGCCACCAACUCCACAUCCtt SEQ ID NO: 1181 CCCACAAAGGCCAGGGAACtt SEQ ID NO: 1182 CGUGAGUUCUGAGAUGCAAtt SEQ ID NO: 1183 AGCUGAUGACAGGCGUGAGtt SEQ ID NO: 1184 CCUCAGGUCCCUCACCUGCtt SEQ ID NO: 1185 UGUGGAGUCCUGGCAGCCAtt SEQ ID NO: 1186 CCCGAUCUUCGUGGUUGCUtt SEQ ID NO: 1187 CGCAACCCGAUCUUCGUGGtt SEQ ID NO: 1188 CCACCCCCGCAACCCGAUCtt SEQ ID NO: 1189 CUGUGGCUUGGGGUCCUCUtt SEQ ID NO: 1190 CAAUAACCCCUCCUGUGGCtt SEQ ID NO: 1191 CACCACCCGAAGCACUUCCtt SEQ ID NO: 1192 CGCCCACCACCCGAAGCACtt SEQ ID NO: 1193 GUGCUCACACUUGAAGGCCtt SEQ ID NO: 1194 GAUACGGCAGUGCUCACACtt SEQ ID NO: 1195 GCUGUGAUAACCACAGAUGtt SEQ ID NO: 1196 GGACAAUGUGGGAAGAGAAtt SEQ ID NO: 1197 GAGAGGUUGCUAGCCCACCtt SEQ ID NO: 1198 CUGAGGAGAGAGGGAGAGGtt SEQ ID NO: 1199 GGCUACAAAGCAAAACUCCtt SEQ ID NO: 1200 AUCUGUUUCAUCACAAUGCtt SEQ ID NO: 1201 ACAUAAGCAAAAGAUCUGUtt SEQ ID NO: 1202 GCAAAAAUAAAUCAACUAAtt SEQ ID NO: 1203 GACUGAUAUAAGUUAAAAUtt SEQ ID NO: 1204 GGCAAGUGACUGAUAUAAGtt SEQ ID NO: 1205 GGCCUAAAGUGGAAAGGAGtt SEQ ID NO: 1206 AAGAUCUAAGAGAGAAAAAtt SEQ ID NO: 1207 UCUUAGUACUAAGAGGAGCtt SEQ ID NO: 1208 GCAAGAAGCUUGAAGUCUCtt SEQ ID NO: 1209 AGGACUUAAAGCAAGAAGCtt SEQ ID NO: 1210 UAAUGUAAAGGGUGAGGACtt SEQ ID NO: 1211 CAGCAUCAAAACUGAAGAAtt SEQ ID NO: 1212 AGAGGUAUGGAGUACCAGGtt SEQ ID NO: 1213 GGAAAUAAUUCUUCAUUCAtt SEQ ID NO: 1214 AUGAGGAAAUAAUUCUUCAtt SEQ ID NO: 1215 CCAAAUGAGGAAAUAAUUCtt SEQ ID NO: 1216 CUUCCAAAUGAGGAAAUAAtt SEQ ID NO: 1217 UUUCUUCAGUCCCUCCUACtt SEQ ID NO: 1218 AGUGCCUGGGGAGAAUUUCtt SEQ ID NO: 1219 CACAGUGCCUGGGGAGAAUtt SEQ ID NO: 1220 ACUAGGGGAAUAUGACCUAtt SEQ ID NO: 1221 UAGGCUUUGAGAACUCAUAtt SEQ ID NO: 1222 GAGAUCCUGAAUGUAGGCUtt SEQ ID NO: 1223 AGAGCGUGUGGAGGGGUAGtt SEQ ID NO: 1224 CACUUAAUAGACCGGUAGGtt SEQ ID NO: 1225 AGGAGAGAAAAGCCACCACtt SEQ ID NO: 1226 GGCCCCUGAGAAUAUAAAAtt SEQ ID NO: 1227 GAGGGUUGCAGACCUAGCCtt SEQ ID NO: 1228 AUCUGUCAGAGACAGAGGGtt SEQ ID NO: 1229 CCCAUGCCCUGGUUCCCAAtt SEQ ID NO: 1230 CUCCUUUCCCAUGCCCUGGtt SEQ ID NO: 1231 AGAAUUUUGACCCACUCCUtt SEQ ID NO: 1232 GAGGAGAAAGAGAAGAAUUtt SEQ ID NO: 1233 UGGAGGAGAAAGAGAAGAAtt SEQ ID NO: 1234 GUCACUAUAGUGAAGAAGUtt SEQ ID NO: 1235 CAGGCAGCAACCCACUAGUtt SEQ ID NO: 1236 GAGGGGCUGAAACAACCCCtt SEQ ID NO: 1237 AGAGAAAAGAGAUACCCGUtt SEQ ID NO: 1238 UUUUUGGUUAUACUGAAAAtt SEQ ID NO: 1239 AUGCUGGGAUAAUUUUUGGtt SEQ ID NO: 1240 GCUCAUGCUGGGAUAAUUUtt SEQ ID NO: 1241 GUGCUCAUGCUGGGAUAAUtt SEQ ID NO: 1242 AGUUGUACCCAUCCCAGUCtt SEQ ID NO: 1243 AAGGAAGACCCCAGUUCAGtt SEQ ID NO: 1244 UAGUAAAGGAAGACCCCAGtt SEQ ID NO: 1245 CCUUCUCACUAAUCCUAGGtt SEQ ID NO: 1246 UUGUAUCUCCUUCUGCCCCtt SEQ ID NO: 1247 GCAGUGGAGUUGUAUCUCCtt SEQ ID NO: 1248 ACCUCCACUUGCAGUGGAGtt SEQ ID NO: 1249 UGUAGAAAGAAACCUCCACtt SEQ ID NO: 1250 GGCCUUGGGCAGAAAACUCtt SEQ ID NO: 1251 GAGUGGGAUGGCUGUGGCCtt SEQ ID NO: 1252 UAGAAAAACAGCCUUUGGUtt SEQ ID NO: 1253 AAACAUAGAAAAACAGCCUtt SEQ ID NO: 1254 UUUUUACUUUUUUUUUUCUtt SEQ ID NO: 1255 UUGGUUUUUACUUUUUUUUtt SEQ ID NO: 1256 GUUUGGUUUUUACUUUUUUtt SEQ ID NO: 1257 GUGUUUGGUUUUUACUUUUtt SEQ ID NO: 1258 UUGUGUUUGGUUUUUACUUtt SEQ ID NO: 1259 UGUUGUGUUUGGUUUUUACtt SEQ ID NO: 1260 GAGGUGUUGUGUUUGGUUUtt SEQ ID NO: 1261 GUGAGGUGUUGUGUUUGGUtt SEQ ID NO: 1262 AACUUGUGAGGUGUUGUGUtt SEQ ID NO: 1263 AGUUACAACUUGUGAGGUGtt SEQ ID NO: 1264 AAGGACCAAGAGUUACAACtt SEQ ID NO: 1265 GAGAGAGAAGGACCAAGAGtt SEQ ID NO: 1266 CUGUUCCUUAGCCCACCCUtt SEQ ID NO: 1267 UAAUCCCAGGGUCUGUUCCtt SEQ ID NO: 1268 GCCCUAAUCCCAGGGUCUGtt SEQ ID NO: 1269 UAGACUCCUCUCAGAGCCCtt SEQ ID NO: 1270 AAGUUUUUUAGGGUCUCCCtt SEQ ID NO: 1271 ACAAAGAGGAGAAAGUUUUtt SEQ ID NO: 1272 GGACAAAGAGGAGAAAGUUtt SEQ ID NO: 1273 GAGGACAAAGAGGAGAAAGtt SEQ ID NO: 1274 CCCUGCCAAUCUGGUUCUCtt SEQ ID NO: 1275 CUUCUCCCUGCCAAUCUGGtt SEQ ID NO: 1276 AACAAUUGCCCCACAAUGCtt SEQ ID NO: 1277 CAUUGUCAAGGAGGAACAAtt SEQ ID NO: 1278 GCAUCUAUUUAUUGCUACAtt SEQ ID NO: 1279 CCUUGGCAGCAUCUAUUUAtt SEQ ID NO: 1280 UGCCCUUGGCAGCAUCUAUtt SEQ ID NO: 1281 ACCUCCCCAUUUUCUGCCCtt SEQ ID NO: 1282 CUGAGCUAACCUCCCCAUUtt SEQ ID NO: 1283 CUCUGAGCUAACCUCCCCAtt SEQ ID NO: 1284 GCCGUUGAGGAUUCUUCCUtt SEQ ID NO: 1285 AGGGUGCCGUUGAGGAUUCtt SEQ ID NO: 1286 CCCAGGGUGCCGUUGAGGAtt SEQ ID NO: 1287 CUAGCACCCCAGGGUGCCGtt SEQ ID NO: 1288 AAUCUCAGCUCUGCUGACAtt SEQ ID NO: 1289 UUCAGGAAAAGCCCAGAUAtt SEQ ID NO: 1290 GGCUCAAUAACCAGAAUAGtt SEQ ID NO: 1291 CCCCAGAAGGGACUAGUCCtt SEQ ID NO: 1292 GAGGUUACAGGUGCCACAGtt SEQ ID NO: 1293 UCCUUCAUGUUCCGGGAGGtt SEQ ID NO: 1294 CAGAGCAUAGUCCUUCAUGtt SEQ ID NO: 1295 UAGCCUCAGAGCAUAGUCCtt SEQ ID NO: 1296 UUAGCACCUGGUCUUGCCCtt SEQ ID NO: 1297 CCCUCCUUAGCACCUGGUCtt SEQ ID NO: 1298 GAUGCCCCCUCUCCCCUCCtt SEQ ID NO: 1299 UUUGUACCUAAGACCCUGGtt SEQ ID NO: 1300 GGCUCUGAAAAGUAGGAUUtt SEQ ID NO: 1301 AAGGCUCUGAAAAGUAGGAtt SEQ ID NO: 1302 AGCAUGAGGAUGUUUGAGGtt SEQ ID NO: 1303 GGAGAGAGCAUGAGGAUGUtt SEQ ID NO: 1304 UUUUUCUUUACUUUUUUUUtt SEQ ID NO: 1305 UCUUUUUCUUUACUUUUUUtt SEQ ID NO: 1306 UUUCUUUUUCUUUACUUUUtt SEQ ID NO: 1307 UUUUUCUUUUUCUUUACUUtt SEQ ID NO: 1308 UUUUUUUCUUUUUCUUUACtt SEQ ID NO: 1309 UAUUUUUUUUUCUUUUUCUtt SEQ ID NO: 1310 UGUGUAUUUUUUUUUCUUUtt SEQ ID NO: 1311 UGUGUGUAUUUUUUUUUCUtt SEQ ID NO: 1312 AGUGUGUGUGUAUUUUUUUtt SEQ ID NO: 1313 UCAGUGUGUGUGUAUUUUUtt SEQ ID NO: 1314 UUUCAGUGUGUGUGUAUUUtt SEQ ID NO: 1315 GGUUUCAGUGUGUGUGUAUtt SEQ ID NO: 1316 CUCUUUUCUCCAUGUGGGUtt SEQ ID NO: 1317 AUAAAAGGAAACACCUCUUtt SEQ ID NO: 1318 AUAUAAAAGGAAACACCUCtt SEQ ID NO: 1319 UUUGUUGGUGGUAUUGAUUtt SEQ ID NO: 1320 AUUUUGUUGGUGGUAUUGAtt SEQ ID NO: 1321 AAAUAUUUUGUUGGUGGUAtt SEQ ID NO: 1322 UCUACUUAGAAAUAUUUUGtt SEQ ID NO: 1323 GUGUCUACUUAGAAAUAUUtt SEQ ID NO: 1324 AAGUGUCUACUUAGAAAUAtt SEQ ID NO: 1325 GGUCUGGAAAAGUGUCUACtt SEQ ID NO: 1326 ACAAAAUCCUAUCUGCAGCtt SEQ ID NO: 1327 AAAGAAGCUGCCAGAAGUAtt SEQ ID NO: 1328 AUAUAUGUAUAUAUAUAUAtt SEQ ID NO: 1329 UGUUCUUCAUAACUUCUGAtt SEQ ID NO: 1330 UCUUUUUGUUCUUCAUAACtt SEQ ID NO: 1331 UUAUUUUUUCUUUUUGUUCtt SEQ ID NO: 1332 UGUUUAUUUUUUCUUUUUGtt SEQ ID NO: 1333 CUGUGUUUAUUUUUUCUUUtt SEQ ID NO: 1334 UUCUGUGUUUAUUUUUUCUtt SEQ ID NO: 1335 UUGCUUCUGUGUUUAUUUUtt SEQ ID NO: 1336 ACUUGCUUCUGUGUUUAUUtt SEQ ID NO: 1337 GCACUUGCUUCUGUGUUUAtt SEQ ID NO: 1338 AUUGCACUUGCUUCUGUGUtt SEQ ID NO: 1339 GAGGUGGUAUUGCACUUGCtt SEQ ID NO: 1340 AAGAGAGGUGGUAUUGCACtt SEQ ID NO: 1341 AGGGAGAAGAGAGGUGGUAtt SEQ ID NO: 1342 GAGAAAGGAGAAAAACUCUtt SEQ ID NO: 1343 AAAGCUAGUUUAACUCCCCtt SEQ ID NO: 1344 AUAAGUCUCAAAAGCUAGUtt SEQ ID NO: 1345 AUUACAUAUACAAAAUGCUtt SEQ ID NO: 1346 AAUAUUUACUUACAAUAUAtt SEQ ID NO: 1347 CCGUUACACAAAUAUUUACtt SEQ ID NO: 1348 AUCUCCGUUACACAAAUAUtt SEQ ID NO: 1349 UUACAGUAGUAUAUCUCCGtt SEQ ID NO: 1350 AGCCAGUACAGUACAAAACtt SEQ ID NO: 1351 UGUUUAUUUAUAACAGACUtt SEQ ID NO: 1352 UUAAAUUACUCAUGUUUAUtt SEQ ID NO: 1353 GGUGUUAAAUUACUCAUGUtt SEQ ID NO: 1354 UUUUUUUUUUGGUGUUAAAtt SEQ ID NO: 1355 UUUUUUUUUUUUUUUGGUGtt SEQ ID NO: 1356 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 1357 GCUGUCCGUGUCCUGGGCCtt SEQ ID NO: 1358 CAGCAUCUGCCUUUCCCUCtt SEQ ID NO: 1359 AAGGGAUGCUGUAGCCUAGtt SEQ ID NO: 1360 GGGAUGCUGUAGCCUAGCAtt SEQ ID NO: 1361 GCACAUCCAAGCGUGCUCUtt SEQ ID NO: 1362 GCGUGCUCUCCCCUCUCCUtt SEQ ID NO: 1363 CACACAUACACCCUGGGCUtt SEQ ID NO: 1364 AUGACGGCGGUUCCCCUCAtt SEQ ID NO: 1365 UCCACGCUUCCUGGAAGGUtt SEQ ID NO: 1366 GGUGAGUGGCUGGGCUCACtt SEQ ID NO: 1367 GGCGGCGGCCGCGUUCGCAtt SEQ ID NO: 1368 GGGAAGGAUAAUCUGGAGAtt SEQ ID NO: 1369 GGAUAAUCUGGAGAGGGAUtt SEQ ID NO: 1370 UCUGGAGAGGGAUCCCUCAtt SEQ ID NO: 1371 GACUCCAACCAUUUUAUAAtt SEQ ID NO: 1372 CCAUUUUAUAAUGGAAUCUtt SEQ ID NO: 1373 UGGAAUCUUUAUUUUGUGAtt SEQ ID NO: 1374 UCUUUAUUUUGUGAAAGUAtt SEQ ID NO: 1375 AGUAGCGGGGACUCAUCUCtt SEQ ID NO: 1376 GGAGUUCCUCGGGGCCCCAtt SEQ ID NO: 1377 CAGCCAGCACUCUUCUCCUtt SEQ ID NO: 1378 CUCCAUCAAGGUGGAGAUGtt SEQ ID NO: 1379 GGUGGAGAUGUACAGCGAUtt SEQ ID NO: 1380 GCAGACUGCUGGGGCCAGAtt SEQ ID NO: 1381 AAGGACGACAGCGUGAUUGtt SEQ ID NO: 1382 GGACGACAGCGUGAUUGUGtt SEQ ID NO: 1383 GAUUCAUUGUCUGAGCCCCtt SEQ ID NO: 1384 UGGCAAGCUCAAGUGUGACtt SEQ ID NO: 1385 GCUCAAGUGUGACGUCUGCtt SEQ ID NO: 1386 GUGUGACGUCUGCGGCAUGtt SEQ ID NO: 1387 CGUGCUCAUGGUGCACAAGtt SEQ ID NO: 1388 GCGCAGUCACACUGGUGAAtt SEQ ID NO: 1389 AGGCCCUUCCAUUGCAACCtt SEQ ID NO: 1390 CCAGUGUGGUGCCUCCUUCtt SEQ ID NO: 1391 GGGGAACCUGCUGCGCCACtt SEQ ID NO: 1392 CCUGCUGCGCCACAUCAAGtt SEQ ID NO: 1393 GCUGCACUCUGGGGAGAAGtt SEQ ID NO: 1394 GCCCUUUAAAUGUCCCUUCtt SEQ ID NO: 1395 AUGUCCCUUCUGCAACUAUtt SEQ ID NO: 1396 CUAUGCCUGCCGCCGGCGUtt SEQ ID NO: 1397 GCCCUACAAGUGUAACUACtt SEQ ID NO: 1398 GUGUAACUACUGUGGCCGGtt SEQ ID NO: 1399 CUACUGUGGCCGGAGCUACtt SEQ ID NO: 1400 ACAGCAGAGUACCCUGGAGtt SEQ ID NO: 1401 GGAGCGGUGCCAUAACUACtt SEQ ID NO: 1402 CUACCUACAGAGUCUCAGCtt SEQ ID NO: 1403 GCCCAAGCUUUGGCUGGCCtt SEQ ID NO: 1404 GCUUUGGCUGGCCAACCAGtt SEQ ID NO: 1405 CCAGGUGACGAAAUACGUGtt SEQ ID NO: 1406 AUACGUGACCUGGAGAUGGtt SEQ ID NO: 1407 CUUUCAUCGAUCGUCUGGCtt SEQ ID NO: 1408 UAGCCUCACCAAACGCAAGtt SEQ ID NO: 1409 ACGCAAGCGUUCCACACCCtt SEQ ID NO: 1410 GCGUUCCACACCCCAGAAGtt SEQ ID NO: 1411 GUUUGUAGGCGAAAAGCAGtt SEQ ID NO: 1412 AAGCAGAUGCGCUUCAGCCtt SEQ ID NO: 1413 GCAGAUGCGCUUCAGCCUCtt SEQ ID NO: 1414 CUCGGGUGGCUAUGAAAAGtt SEQ ID NO: 1415 AAGGAUGUGGAGUUGGUGGtt SEQ ID NO: 1416 GGAUGUGGAGUUGGUGGCAtt SEQ ID NO: 1417 GUUCCCUGGCCUUUGUGGGtt SEQ ID NO: 1418 UUGCAUCUCAGAACUCACGtt SEQ ID NO: 1419 CUCACGCCUGUCAUCAGCUtt SEQ ID NO: 1420 GCAGGUGAGGGACCUGAGGtt SEQ ID NO: 1421 UGGCUGCCAGGACUCCACAtt SEQ ID NO: 1422 AGCAACCACGAAGAUCGGGtt SEQ ID NO: 1423 CCACGAAGAUCGGGUUGCGtt SEQ ID NO: 1424 GAUCGGGUUGCGGGGGUGGtt SEQ ID NO: 1425 AGAGGACCCCAAGCCACAGtt SEQ ID NO: 1426 GCCACAGGAGGGGUUAUUGtt SEQ ID NO: 1427 GGAAGUGCUUCGGGUGGUGtt SEQ ID NO: 1428 GUGCUUCGGGUGGUGGGCGtt SEQ ID NO: 1429 GGCCUUCAAGUGUGAGCACtt SEQ ID NO: 1430 GUGUGAGCACUGCCGUAUCtt SEQ ID NO: 1431 CAUCUGUGGUUAUCACAGCtt SEQ ID NO: 1432 UUCUCUUCCCACAUUGUCCtt SEQ ID NO: 1433 GGUGGGCUAGCAACCUCUCtt SEQ ID NO: 1434 CCUCUCCCUCUCUCCUCAGtt SEQ ID NO: 1435 GGAGUUUUGCUUUGUAGCCtt SEQ ID NO: 1436 GCAUUGUGAUGAAACAGAUtt SEQ ID NO: 1437 ACAGAUCUUUUGCUUAUGUtt SEQ ID NO: 1438 UUAGUUGAUUUAUUUUUGCtt SEQ ID NO: 1439 AUUUUAACUUAUAUCAGUCtt SEQ ID NO: 1440 CUUAUAUCAGUCACUUGCCtt SEQ ID NO: 1441 CUCCUUUCCACUUUAGGCCtt SEQ ID NO: 1442 UUUUUCUCUCUUAGAUCUUtt SEQ ID NO: 1443 GCUCCUCUUAGUACUAAGAtt SEQ ID NO: 1444 GAGACUUCAAGCUUCUUGCtt SEQ ID NO: 1445 GCUUCUUGCUUUAAGUCCUtt SEQ ID NO: 1446 GUCCUCACCCUUUACAUUAtt SEQ ID NO: 1447 UUCUUCAGUUUUGAUGCUGtt SEQ ID NO: 1448 CCUGGUACUCCAUACCUCUtt SEQ ID NO: 1449 UGAAUGAAGAAUUAUUUCCtt SEQ ID NO: 1450 UGAAGAAUUAUUUCCUCAUtt SEQ ID NO: 1451 GAAUUAUUUCCUCAUUUGGtt SEQ ID NO: 1452 UUAUUUCCUCAUUUGGAAGtt SEQ ID NO: 1453 GUAGGAGGGACUGAAGAAAtt SEQ ID NO: 1454 GAAAUUCUCCCCAGGCACUtt SEQ ID NO: 1455 AUUCUCCCCAGGCACUGUGtt SEQ ID NO: 1456 UAGGUCAUAUUCCCCUAGUtt SEQ ID NO: 1457 UAUGAGUUCUCAAAGCCUAtt SEQ ID NO: 1458 AGCCUACAUUCAGGAUCUCtt SEQ ID NO: 1459 CUACCCCUCCACACGCUCUtt SEQ ID NO: 1460 CCUACCGGUCUAUUAAGUGtt SEQ ID NO: 1461 GUGGUGGCUUUUCUCUCCUtt SEQ ID NO: 1462 UUUUAUAUUCUCAGGGGCCtt SEQ ID NO: 1463 GGCUAGGUCUGCAACCCUCtt SEQ ID NO: 1464 CCCUCUGUCUCUGACAGAUtt SEQ ID NO: 1465 UUGGGAACCAGGGCAUGGGtt SEQ ID NO: 1466 CCAGGGCAUGGGAAAGGAGtt SEQ ID NO: 1467 AGGAGUGGGUCAAAAUUCUtt SEQ ID NO: 1468 AAUUCUUCUCUUUCUCCUCtt SEQ ID NO: 1469 UUCUUCUCUUUCUCCUCCAtt SEQ ID NO: 1470 ACUUCUUCACUAUAGUGACtt SEQ ID NO: 1471 ACUAGUGGGUUGCUGCCUGtt SEQ ID NO: 1472 GGGGUUGUUUCAGCCCCUCtt SEQ ID NO: 1473 ACGGGUAUCUCUUUUCUCUtt SEQ ID NO: 1474 UUUUCAGUAUAACCAAAAAtt SEQ ID NO: 1475 CCAAAAAUUAUCCCAGCAUtt SEQ ID NO: 1476 AAAUUAUCCCAGCAUGAGCtt SEQ ID NO: 1477 AUUAUCCCAGCAUGAGCACtt SEQ ID NO: 1478 GACUGGGAUGGGUACAACUtt SEQ ID NO: 1479 CUGAACUGGGGUCUUCCUUtt SEQ ID NO: 1480 CUGGGGUCUUCCUUUACUAtt SEQ ID NO: 1481 CCUAGGAUUAGUGAGAAGGtt SEQ ID NO: 1482 GGGGCAGAAGGAGAUACAAtt SEQ ID NO: 1483 GGAGAUACAACUCCACUGCtt SEQ ID NO: 1484 CUCCACUGCAAGUGGAGGUtt SEQ ID NO: 1485 GUGGAGGUUUCUUUCUACAtt SEQ ID NO: 1486 GAGUUUUCUGCCCAAGGCCtt SEQ ID NO: 1487 GGCCACAGCCAUCCCACUCtt SEQ ID NO: 1488 ACCAAAGGCUGUUUUUCUAtt SEQ ID NO: 1489 AGGCUGUUUUUCUAUGUUUtt SEQ ID NO: 1490 AGAAAAAAAAAAGUAAAAAtt SEQ ID NO: 1491 AAAAAAAAGUAAAAACCAAtt SEQ ID NO: 1492 AAAAAAGUAAAAACCAAACtt SEQ ID NO: 1493 AAAAGUAAAAACCAAACACtt SEQ ID NO: 1494 AAGUAAAAACCAAACACAAtt SEQ ID NO: 1495 GUAAAAACCAAACACAACAtt SEQ ID NO: 1496 AAACCAAACACAACACCUCtt SEQ ID NO: 1497 ACCAAACACAACACCUCACtt SEQ ID NO: 1498 ACACAACACCUCACAAGUUtt SEQ ID NO: 1499 CACCUCACAAGUUGUAACUtt SEQ ID NO: 1500 GUUGUAACUCUUGGUCCUUtt SEQ ID NO: 1501 CUCUUGGUCCUUCUCUCUCtt SEQ ID NO: 1502 AGGGUGGGCUAAGGAACAGtt SEQ ID NO: 1503 GGAACAGACCCUGGGAUUAtt SEQ ID NO: 1504 CAGACCCUGGGAUUAGGGCtt SEQ ID NO: 1505 GGGCUCUGAGAGGAGUCUAtt SEQ ID NO: 1506 GGGAGACCCUAAAAAACUUtt SEQ ID NO: 1507 AAAACUUUCUCCUCUUUGUtt SEQ ID NO: 1508 AACUUUCUCCUCUUUGUCCtt SEQ ID NO: 1509 CUUUCUCCUCUUUGUCCUCtt SEQ ID NO: 1510 GAGAACCAGAUUGGCAGGGtt SEQ ID NO: 1511 CCAGAUUGGCAGGGAGAAGtt SEQ ID NO: 1512 GCAUUGUGGGGCAAUUGUUtt SEQ ID NO: 1513 UUGUUCCUCCUUGACAAUGtt SEQ ID NO: 1514 UGUAGCAAUAAAUAGAUGCtt SEQ ID NO: 1515 UAAAUAGAUGCUGCCAAGGtt SEQ ID NO: 1516 AUAGAUGCUGCCAAGGGCAtt SEQ ID NO: 1517 GGGCAGAAAAUGGGGAGGUtt SEQ ID NO: 1518 AAUGGGGAGGUUAGCUCAGtt SEQ ID NO: 1519 UGGGGAGGUUAGCUCAGAGtt SEQ ID NO: 1520 AGGAAGAAUCCUCAACGGCtt SEQ ID NO: 1521 GAAUCCUCAACGGCACCCUtt SEQ ID NO: 1522 UCCUCAACGGCACCCUGGGtt SEQ ID NO: 1523 CGGCACCCUGGGGUGCUAGtt SEQ ID NO: 1524 UGUCAGCAGAGCUGAGAUUtt SEQ ID NO: 1525 UAUCUGGGCUUUUCCUGAAtt SEQ ID NO: 1526 CUAUUCUGGUUAUUGAGCCtt SEQ ID NO: 1527 GGACUAGUCCCUUCUGGGGtt SEQ ID NO: 1528 CUGUGGCACCUGUAACCUCtt SEQ ID NO: 1529 CCUCCCGGAACAUGAAGGAtt SEQ ID NO: 1530 CAUGAAGGACUAUGCUCUGtt SEQ ID NO: 1531 GGACUAUGCUCUGAGGCUAtt SEQ ID NO: 1532 GGGCAAGACCAGGUGCUAAtt SEQ ID NO: 1533 GACCAGGUGCUAAGGAGGGtt SEQ ID NO: 1534 GGAGGGGAGAGGGGGCAUCtt SEQ ID NO: 1535 CCAGGGUCUUAGGUACAAAtt SEQ ID NO: 1536 AAUCCUACUUUUCAGAGCCtt SEQ ID NO: 1537 UCCUACUUUUCAGAGCCUUtt SEQ ID NO: 1538 CCUCAAACAUCCUCAUGCUtt SEQ ID NO: 1539 ACAUCCUCAUGCUCUCUCCtt SEQ ID NO: 1540 AAAAAAAAGUAAAGAAAAAtt SEQ ID NO: 1541 AAAAAAGUAAAGAAAAAGAtt SEQ ID NO: 1542 AAAAGUAAAGAAAAAGAAAtt SEQ ID NO: 1543 AAGUAAAGAAAAAGAAAAAtt SEQ ID NO: 1544 GUAAAGAAAAAGAAAAAAAtt SEQ ID NO: 1545 AGAAAAAGAAAAAAAAAUAtt SEQ ID NO: 1546 AAAGAAAAAAAAAUACACAtt SEQ ID NO: 1547 AGAAAAAAAAAUACACACAtt SEQ ID NO: 1548 AAAAAAAUACACACACACUtt SEQ ID NO: 1549 AAAAAUACACACACACUGAtt SEQ ID NO: 1550 AAAUACACACACACUGAAAtt SEQ ID NO: 1551 AUACACACACACUGAAACCtt SEQ ID NO: 1552 ACCCACAUGGAGAAAAGAGtt SEQ ID NO: 1553 AAGAGGUGUUUCCUUUUAUtt SEQ ID NO: 1554 GAGGUGUUUCCUUUUAUAUtt SEQ ID NO: 1555 AAUCAAUACCACCAACAAAtt SEQ ID NO: 1556 UCAAUACCACCAACAAAAUtt SEQ ID NO: 1557 UACCACCAACAAAAUAUUUtt SEQ ID NO: 1558 CAAAAUAUUUCUAAGUAGAtt SEQ ID NO: 1559 AAUAUUUCUAAGUAGACACtt SEQ ID NO: 1560 UAUUUCUAAGUAGACACUUtt SEQ ID NO: 1561 GUAGACACUUUUCCAGACCtt SEQ ID NO: 1562 GCUGCAGAUAGGAUUUUGUtt SEQ ID NO: 1563 UACUUCUGGCAGCUUCUUUtt SEQ ID NO: 1564 UAUAUAUAUAUACAUAUAUtt SEQ ID NO: 1565 UCAGAAGUUAUGAAGAACAtt SEQ ID NO: 1566 GUUAUGAAGAACAAAAAGAtt SEQ ID NO: 1567 GAACAAAAAGAAAAAAUAAtt SEQ ID NO: 1568 CAAAAAGAAAAAAUAAACAtt SEQ ID NO: 1569 AAAGAAAAAAUAAACACAGtt SEQ ID NO: 1570 AGAAAAAAUAAACACAGAAtt SEQ ID NO: 1571 AAAAUAAACACAGAAGCAAtt SEQ ID NO: 1572 AAUAAACACAGAAGCAAGUtt SEQ ID NO: 1573 UAAACACAGAAGCAAGUGCtt SEQ ID NO: 1574 ACACAGAAGCAAGUGCAAUtt SEQ ID NO: 1575 GCAAGUGCAAUACCACCUCtt SEQ ID NO: 1576 GUGCAAUACCACCUCUCUUtt SEQ ID NO: 1577 UACCACCUCUCUUCUCCCUtt SEQ ID NO: 1578 AGAGUUUUUCUCCUUUCUCtt SEQ ID NO: 1579 GGGGAGUUAAACUAGCUUUtt SEQ ID NO: 1580 ACUAGCUUUUGAGACUUAUtt SEQ ID NO: 1581 AGCAUUUUGUAUAUGUAAUtt SEQ ID NO: 1582 UAUAUUGUAAGUAAAUAUUtt SEQ ID NO: 1583 GUAAAUAUUUGUGUAACGGtt SEQ ID NO: 1584 AUAUUUGUGUAACGGAGAUtt SEQ ID NO: 1585 CGGAGAUAUACUACUGUAAtt SEQ ID NO: 1586 GUUUUGUACUGUACUGGCUtt SEQ ID NO: 1587 AGUCUGUUAUAAAUAAACAtt SEQ ID NO: 1588 AUAAACAUGAGUAAUUUAAtt SEQ ID NO: 1589 ACAUGAGUAAUUUAACACCtt SEQ ID NO: 1590 UUUAACACCAAAAAAAAAAtt SEQ ID NO: 1591 CACCAAAAAAAAAAAAAAAtt SEQ ID NO: 1592 AAAAAAAAAAAAAAAAAAAtt

TABLE 8 Candidate siRNAs for RAB5B, SEQ ID NOs: 1593-1912 are based on NM_002868. SEQ ID NO: 1593 GGGGAGGGGAUUUCCAGGCtt SEQ ID NO: 1594 AGGGGGAAGGGGAGGGGAUtt SEQ ID NO: 1595 UCUGCUAGUCAUGGCCAGAtt SEQ ID NO: 1596 CCAUUGGGCCUAGCUGUGCtt SEQ ID NO: 1597 GCUGGCCUGGGGUUGCCCAtt SEQ ID NO: 1598 AAAUUUUGCUGGCCUGGGGtt SEQ ID NO: 1599 CAAUUUGAACUGGCAAAUUtt SEQ ID NO: 1600 ACCAAUUUGAACUGGCAAAtt SEQ ID NO: 1601 UUCUCCCAGCAGGACCAAUtt SEQ ID NO: 1602 UUGACUUUCCCACUGCAGAtt SEQ ID NO: 1603 CGUAAUACCAGGCUUGACUtt SEQ ID NO: 1604 ACAAAACGUAAUACCAGGCtt SEQ ID NO: 1605 GUACUCAUGGAACUGCCCUtt SEQ ID NO: 1606 CAGAUCUCAAACUUCACUGtt SEQ ID NO: 1607 UGUGUCCCAGAUCUCAAACtt SEQ ID NO: 1608 CGUAAACCACGAUUGCAGCtt SEQ ID NO: 1609 GUAAUGUCGUAAACCACGAtt SEQ ID NO: 1610 UCGGGCAAAGGUUUCCUGAtt SEQ ID NO: 1611 UCUUUGCUCGGGCAAAGGUtt SEQ ID NO: 1612 AGUUCCUUCACCCAUGUCUtt SEQ ID NO: 1613 GGCCUGUCGCUGUAGUUCCtt SEQ ID NO: 1614 GACUGGCCUGUCGCUGUAGtt SEQ ID NO: 1615 GUUGGCCAGGUCAGCUUUGtt SEQ ID NO: 1616 UUUGUUGGCCAGGUCAGCUtt SEQ ID NO: 1617 AUACUCCACCAUACGUUUGtt SEQ ID NO: 1618 UUCAUACUCCACCAUACGUtt SEQ ID NO: 1619 CUGCAUAUGCCUGGGCCUCtt SEQ ID NO: 1620 CUCCAUGAACAAUAAGCUGtt SEQ ID NO: 1621 AUUCACGUUCAUAGCUGUCtt SEQ ID NO: 1622 CAGGAAGAGAUCAUUCACGtt SEQ ID NO: 1623 UAUUGCCAGGAAGAGAUCAtt SEQ ID NO: 1624 UUUGGCAACUUCUUAGCUAtt SEQ ID NO: 1625 UUCACUCUUUGGCAACUUCtt SEQ ID NO: 1626 GGGUUCACUCUUUGGCAACtt SEQ ID NO: 1627 AGAUUCUGGGGUUCACUCUtt SEQ ID NO: 1628 CACCUCCCAGAUUCUGGGGtt SEQ ID NO: 1629 GCCUGCUGCACCUCCCAGAtt SEQ ID NO: 1630 UGGAGAUCCACACCCCGGCtt SEQ ID NO: 1631 UCUUGUUCUGCUGGGACUGtt SEQ ID NO: 1632 GCUACAACACUGGCUCUUGtt SEQ ID NO: 1633 GUUGCUACAACACUGGCUCtt SEQ ID NO: 1634 CUGCUAGCCACCCCCUCAGtt SEQ ID NO: 1635 GUGCUAGCUCCAUACUUGUtt SEQ ID NO: 1636 UCUUGUGCUAGCUCCAUACtt SEQ ID NO: 1637 GGAGGUUAUUUCUUAGCUCtt SEQ ID NO: 1638 UAGGGAUGGAGGUUAUUUCtt SEQ ID NO: 1639 GGGUAGGGAUGGAGGUUAUtt SEQ ID NO: 1640 UGAGGGGUAGGGAUGGAGGtt SEQ ID NO: 1641 UGUGCUGUUACCGUAGGGGtt SEQ ID NO: 1642 GCCAGGGCUCAGUGUGCUGtt SEQ ID NO: 1643 AGCUGUCAGGAGGCAGCCCtt SEQ ID NO: 1644 GGUGUUUGUUGCUGAAGCGtt SEQ ID NO: 1645 AACAGCUGCCUGGUGUUUGtt SEQ ID NO: 1646 GGCAACAGCUGCCUGGUGUtt SEQ ID NO: 1647 AGGUAAGUCCUGGGGGGAGtt SEQ ID NO: 1648 AAAGUGAAGAAAGUUUGUUtt SEQ ID NO: 1649 ACAAAGUGAAGAAAGUUUGtt SEQ ID NO: 1650 AAUACAAAGUGAAGAAAGUtt SEQ ID NO: 1651 AGAUACGUAAGUCGCUGUCtt SEQ ID NO: 1652 GACAGGAGUCAGAAGUGUUtt SEQ ID NO: 1653 GGGACAGGAGUCAGAAGUGtt SEQ ID NO: 1654 AGUUCCUGGGUUCACCACUtt SEQ ID NO: 1655 UCCUUCCUCAGUUCCUGGGtt SEQ ID NO: 1656 UGGAAACCUCCUUCCUCAGtt SEQ ID NO: 1657 AAAUGAACUGGAAACCUCCtt SEQ ID NO: 1658 UUAUUCUCCCCCAGGGCCCtt SEQ ID NO: 1659 CCUCCUGCUCUGAGCUUUAtt SEQ ID NO: 1660 CUCCCUCCUGCUCUGAGCUtt SEQ ID NO: 1661 ACAAAAAGGAAAUGUUUCCtt SEQ ID NO: 1662 AAAAACAAAAAGGAAAUGUtt SEQ ID NO: 1663 UCAUGGAUACCGCAAUGUUtt SEQ ID NO: 1664 AAUCAUGGAUACCGCAAUGtt SEQ ID NO: 1665 CUGAGAUCUUGCCUCCCCAtt SEQ ID NO: 1666 CUGCCUGGUGCCUGAGAUCtt SEQ ID NO: 1667 CCACCUCCGCCCAGUUAGCtt SEQ ID NO: 1668 CACCUCCACCUCCGCCCAGtt SEQ ID NO: 1669 AAGAGUUACAGAGCCACAGtt SEQ ID NO: 1670 AAACUGGGCCUUUGAAGAGtt SEQ ID NO: 1671 GUGAGGGGAAACUGGGCCUtt SEQ ID NO: 1672 UGGGGUCCAACCCCCACGAtt SEQ ID NO: 1673 GGCAACCAGUGAAAAUUCUtt SEQ ID NO: 1674 UGCAGGCAACCAGUGAAAAtt SEQ ID NO: 1675 CCAACUGAACUACCAUCAAtt SEQ ID NO: 1676 CAAGUAAAUCAAUCAAAACtt SEQ ID NO: 1677 AACCUCAGAUUUCAUUGAAtt SEQ ID NO: 1678 GCAUUAACCUCAGAUUUCAtt SEQ ID NO: 1679 CCUCGCAUUAACCUCAGAUtt SEQ ID NO: 1680 CCUCUCCUCGAACCUCGCAtt SEQ ID NO: 1681 GUAGCUGCCACUGGUAGUUtt SEQ ID NO: 1682 GAGUAGCUGCCACUGGUAGtt SEQ ID NO: 1683 CUAACAGUGGAGAUAGGACtt SEQ ID NO: 1684 UAUAGGUUAAUAAUUAGAGtt SEQ ID NO: 1685 CAAGAAUAUAGGUUAAUAAtt SEQ ID NO: 1686 AGCUUGGCAAGAAUAUAGGtt SEQ ID NO: 1687 CCUAUAGUCAAUAGUUAGCtt SEQ ID NO: 1688 GCAAACCUAUAGUCAAUAGtt SEQ ID NO: 1689 UCCUCAAUUGCUCAAUUAAtt SEQ ID NO: 1690 ACACUCCUCAAUUGCUCAAtt SEQ ID NO: 1691 AUCCUGAGACACUCCUCAAtt SEQ ID NO: 1692 UCCUUUUUACUCCCCUACCtt SEQ ID NO: 1693 CUUUUGCCUGACCUCCUUUtt SEQ ID NO: 1694 CCCUUUUGCCUGACCUCCUtt SEQ ID NO: 1695 GACAGAAAACUCCUCCCUUtt SEQ ID NO: 1696 AGGACAGAAAACUCCUCCCtt SEQ ID NO: 1697 CAUGGUAAUGGAUAUCAAAtt SEQ ID NO: 1698 GAAUAAAGAUCAUACCUAUtt SEQ ID NO: 1699 AGGGACUAAAUUCAAGAUAtt SEQ ID NO: 1700 UAAGGAUGGAGGGACUAAAtt SEQ ID NO: 1701 AUGGGGAGGGAUGGGGGGAtt SEQ ID NO: 1702 ACAUGGAUUAAACCACUGGtt SEQ ID NO: 1703 GCCCCUAUUGGUACAUGGAtt SEQ ID NO: 1704 UCUGUGGUACUAGCCCCUAtt SEQ ID NO: 1705 GUACCUUCAGUGCCGGUCAtt SEQ ID NO: 1706 GAGCCAGUUGUAAGGUACCtt SEQ ID NO: 1707 CUCUGAUAAUAUGAGCCAGtt SEQ ID NO: 1708 AUGAAGAGAGACUAGAGAUtt SEQ ID NO: 1709 AUGGCUUCUCAGAGACAUCtt SEQ ID NO: 1710 UCUCUUUUGCCUUGAUGGCtt SEQ ID NO: 1711 CUUAAAGUUCUCUUUUGCCtt SEQ ID NO: 1712 AGGAACUUAAAGUUCUCUUtt SEQ ID NO: 1713 CAAGGAACUUAAAGUUCUCtt SEQ ID NO: 1714 UGGAACAAGGAACUUAAAGtt SEQ ID NO: 1715 CCGGGCUGGAACAAGGAACtt SEQ ID NO: 1716 UGACCUUUCCUUUCUUUCUtt SEQ ID NO: 1717 ACUGUGACCUUUCCUUUCUtt SEQ ID NO: 1718 GGUCACUGUGACCUUUCCUtt SEQ ID NO: 1719 UCCUAGGUCACUGUGACCUtt SEQ ID NO: 1720 AGCCAAAAGGGCAGGAAGGtt SEQ ID NO: 1721 UUCAUAGAUUUCUCAGCUGtt SEQ ID NO: 1722 GAAUCUCAGCUUCAUAGAUtt SEQ ID NO: 1723 GGUCCUUCAGAAUCUCAGCtt SEQ ID NO: 1724 AAGAACCUAAGCUGGGUCCtt SEQ ID NO: 1725 CCCUGGAAAAGGAAGGGAAtt SEQ ID NO: 1726 AAGGGGGAAAUGUGUGUGUtt SEQ ID NO: 1727 GCUAUGGGGGGCCAGUGGCtt SEQ ID NO: 1728 GCCAUCCUAGUUCUUCCACtt SEQ ID NO: 1729 UGGAAAGCCAUCCUAGUUCtt SEQ ID NO: 1730 CUUUGGAAAGCCAUCCUAGtt SEQ ID NO: 1731 ACUUCAUUUCUAGAAGACUtt SEQ ID NO: 1732 CACAGAGAAAGAACUUCAUtt SEQ ID NO: 1733 AGCUGCACAGAGAAAGAACtt SEQ ID NO: 1734 CCCAAGAUAAUGAAACAUCtt SEQ ID NO: 1735 AGAAGCCUGGGGAAGUGGUtt SEQ ID NO: 1736 AAGCUAAGGCCAAAUCCUGtt SEQ ID NO: 1737 AAAACCACAACACCCCCCCtt SEQ ID NO: 1738 AGGAAGAAAGGCAAAUGCUtt SEQ ID NO: 1739 UGUUACCACGAUUGUUAUGtt SEQ ID NO: 1740 CAUUCUGUUACCACGAUUGtt SEQ ID NO: 1741 UCGCAUUCUGUUACCACGAtt SEQ ID NO: 1742 AAUCAGCAGUCGCAUUCUGtt SEQ ID NO: 1743 CGGUAAAUCAGCAGUCGCAtt SEQ ID NO: 1744 UUUCCUUUUUUUACUUACAtt SEQ ID NO: 1745 CUUUUUUUCCUUUUUUUACtt SEQ ID NO: 1746 UUUUCUUUUUUUCCUUUUUtt SEQ ID NO: 1747 UUUUUUCUUUUUUUCCUUUtt SEQ ID NO: 1748 UUUUUUUUCUUUUUUUCCUtt SEQ ID NO: 1749 UUUUUUUUUUUUUCUUUUUtt SEQ ID NO: 1750 UUUUUUUUUUUUUUUCUUUtt SEQ ID NO: 1751 UUUUUUUUUUUUUUUUUCUtt SEQ ID NO: 1752 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 1753 GCCUGGAAAUCCCCUCCCCtt SEQ ID NO: 1754 AUCCCCUCCCCUUCCCCCUtt SEQ ID NO: 1755 UCUGGCCAUGACUAGCAGAtt SEQ ID NO: 1756 GCACAGCUAGGCCCAAUGGtt SEQ ID NO: 1757 UGGGCAACCCCAGGCCAGCtt SEQ ID NO: 1758 CCCCAGGCCAGCAAAAUUUtt SEQ ID NO: 1759 AAUUUGCCAGUUCAAAUUGtt SEQ ID NO: 1760 UUUGCCAGUUCAAAUUGGUtt SEQ ID NO: 1761 AUUGGUCCUGCUGGGAGAAtt SEQ ID NO: 1762 UCUGCAGUGGGAAAGUCAAtt SEQ ID NO: 1763 AGUCAAGCCUGGUAUUACGtt SEQ ID NO: 1764 GCCUGGUAUUACGUUUUGUtt SEQ ID NO: 1765 AGGGCAGUUCCAUGAGUACtt SEQ ID NO: 1766 CAGUGAAGUUUGAGAUCUGtt SEQ ID NO: 1767 GUUUGAGAUCUGGGACACAtt SEQ ID NO: 1768 GCUGCAAUCGUGGUUUACGtt SEQ ID NO: 1769 UCGUGGUUUACGACAUUACtt SEQ ID NO: 1770 UCAGGAAACCUUUGCCCGAtt SEQ ID NO: 1771 ACCUUUGCCCGAGCAAAGAtt SEQ ID NO: 1772 AGACAUGGGUGAAGGAACUtt SEQ ID NO: 1773 GGAACUACAGCGACAGGCCtt SEQ ID NO: 1774 CUACAGCGACAGGCCAGUCtt SEQ ID NO: 1775 CAAAGCUGACCUGGCCAACtt SEQ ID NO: 1776 AGCUGACCUGGCCAACAAAtt SEQ ID NO: 1777 CAAACGUAUGGUGGAGUAUtt SEQ ID NO: 1778 ACGUAUGGUGGAGUAUGAAtt SEQ ID NO: 1779 GAGGCCCAGGCAUAUGCAGtt SEQ ID NO: 1780 CAGCUUAUUGUUCAUGGAGtt SEQ ID NO: 1781 GACAGCUAUGAACGUGAAUtt SEQ ID NO: 1782 CGUGAAUGAUCUCUUCCUGtt SEQ ID NO: 1783 UGAUCUCUUCCUGGCAAUAtt SEQ ID NO: 1784 UAGCUAAGAAGUUGCCAAAtt SEQ ID NO: 1785 GAAGUUGCCAAAGAGUGAAtt SEQ ID NO: 1786 GUUGCCAAAGAGUGAACCCtt SEQ ID NO: 1787 AGAGUGAACCCCAGAAUCUtt SEQ ID NO: 1788 CCCCAGAAUCUGGGAGGUGtt SEQ ID NO: 1789 UCUGGGAGGUGCAGCAGGCtt SEQ ID NO: 1790 GCCGGGGUGUGGAUCUCCAtt SEQ ID NO: 1791 CAGUCCCAGCAGAACAAGAtt SEQ ID NO: 1792 CAAGAGCCAGUGUUGUAGCtt SEQ ID NO: 1793 GAGCCAGUGUUGUAGCAACtt SEQ ID NO: 1794 CUGAGGGGGUGGCUAGCAGtt SEQ ID NO: 1795 ACAAGUAUGGAGCUAGCACtt SEQ ID NO: 1796 GUAUGGAGCUAGCACAAGAtt SEQ ID NO: 1797 GAGCUAAGAAAUAACCUCCtt SEQ ID NO: 1798 GAAAUAACCUCCAUCCCUAtt SEQ ID NO: 1799 AUAACCUCCAUCCCUACCCtt SEQ ID NO: 1800 CCUCCAUCCCUACCCCUCAtt SEQ ID NO: 1801 CCCCUACGGUAACAGCACAtt SEQ ID NO: 1802 CAGCACACUGAGCCCUGGCtt SEQ ID NO: 1803 GGGCUGCCUCCUGACAGCUtt SEQ ID NO: 1804 CGCUUCAGCAACAAACACCtt SEQ ID NO: 1805 CAAACACCAGGCAGCUGUUtt SEQ ID NO: 1806 ACACCAGGCAGCUGUUGCCtt SEQ ID NO: 1807 CUCCCCCCAGGACUUACCUtt SEQ ID NO: 1808 AACAAACUUUCUUCACUUUtt SEQ ID NO: 1809 CAAACUUUCUUCACUUUGUtt SEQ ID NO: 1810 ACUUUCUUCACUUUGUAUUtt SEQ ID NO: 1811 GACAGCGACUUACGUAUCUtt SEQ ID NO: 1812 AACACUUCUGACUCCUGUCtt SEQ ID NO: 1813 CACUUCUGACUCCUGUCCCtt SEQ ID NO: 1814 AGUGGUGAACCCAGGAACUtt SEQ ID NO: 1815 CCCAGGAACUGAGGAAGGAtt SEQ ID NO: 1816 CUGAGGAAGGAGGUUUCCAtt SEQ ID NO: 1817 GGAGGUUUCCAGUUCAUUUtt SEQ ID NO: 1818 GGGCCCUGGGGGAGAAUAAtt SEQ ID NO: 1819 UAAAGCUCAGAGCAGGAGGtt SEQ ID NO: 1820 AGCUCAGAGCAGGAGGGAGtt SEQ ID NO: 1821 GGAAACAUUUCCUUUUUGUtt SEQ ID NO: 1822 ACAUUUCCUUUUUGUUUUUtt SEQ ID NO: 1823 AACAUUGCGGUAUCCAUGAtt SEQ ID NO: 1824 CAUUGCGGUAUCCAUGAUUtt SEQ ID NO: 1825 UGGGGAGGCAAGAUCUCAGtt SEQ ID NO: 1826 GAUCUCAGGCACCAGGCAGtt SEQ ID NO: 1827 GCUAACUGGGCGGAGGUGGtt SEQ ID NO: 1828 CUGGGCGGAGGUGGAGGUGtt SEQ ID NO: 1829 CUGUGGCUCUGUAACUCUUtt SEQ ID NO: 1830 CUCUUCAAAGGCCCAGUUUtt SEQ ID NO: 1831 AGGCCCAGUUUCCCCUCACtt SEQ ID NO: 1832 UCGUGGGGGUUGGACCCCAtt SEQ ID NO: 1833 AGAAUUUUCACUGGUUGCCtt SEQ ID NO: 1834 UUUUCACUGGUUGCCUGCAtt SEQ ID NO: 1835 UUGAUGGUAGUUCAGUUGGtt SEQ ID NO: 1836 GUUUUGAUUGAUUUACUUGtt SEQ ID NO: 1837 UUCAAUGAAAUCUGAGGUUtt SEQ ID NO: 1838 UGAAAUCUGAGGUUAAUGCtt SEQ ID NO: 1839 AUCUGAGGUUAAUGCGAGGtt SEQ ID NO: 1840 UGCGAGGUUCGAGGAGAGGtt SEQ ID NO: 1841 AACUACCAGUGGCAGCUACtt SEQ ID NO: 1842 CUACCAGUGGCAGCUACUCtt SEQ ID NO: 1843 GUCCUAUCUCCACUGUUAGtt SEQ ID NO: 1844 CUCUAAUUAUUAACCUAUAtt SEQ ID NO: 1845 UUAUUAACCUAUAUUCUUGtt SEQ ID NO: 1846 CCUAUAUUCUUGCCAAGCUtt SEQ ID NO: 1847 GCUAACUAUUGACUAUAGGtt SEQ ID NO: 1848 CUAUUGACUAUAGGUUUGCtt SEQ ID NO: 1849 UUAAUUGAGCAAUUGAGGAtt SEQ ID NO: 1850 UUGAGCAAUUGAGGAGUGUtt SEQ ID NO: 1851 UUGAGGAGUGUCUCAGGAUtt SEQ ID NO: 1852 GGUAGGGGAGUAAAAAGGAtt SEQ ID NO: 1853 AAAGGAGGUCAGGCAAAAGtt SEQ ID NO: 1854 AGGAGGUCAGGCAAAAGGGtt SEQ ID NO: 1855 AAGGGAGGAGUUUUCUGUCtt SEQ ID NO: 1856 GGGAGGAGUUUUCUGUCCUtt SEQ ID NO: 1857 UUUGAUAUCCAUUACCAUGtt SEQ ID NO: 1858 AUAGGUAUGAUCUUUAUUCtt SEQ ID NO: 1859 UAUCUUGAAUUUAGUCCCUtt SEQ ID NO: 1860 UUUAGUCCCUCCAUCCUUAtt SEQ ID NO: 1861 UCCCCCCAUCCCUCCCCAUtt SEQ ID NO: 1862 CCAGUGGUUUAAUCCAUGUtt SEQ ID NO: 1863 UCCAUGUACCAAUAGGGGCtt SEQ ID NO: 1864 UAGGGGCUAGUACCACAGAtt SEQ ID NO: 1865 UGACCGGCACUGAAGGUACtt SEQ ID NO: 1866 GGUACCUUACAACUGGCUCtt SEQ ID NO: 1867 CUGGCUCAUAUUAUCAGAGtt SEQ ID NO: 1868 AUCUCUAGUCUCUCUUCAUtt SEQ ID NO: 1869 GAUGUCUCUGAGAAGCCAUtt SEQ ID NO: 1870 GCCAUCAAGGCAAAAGAGAtt SEQ ID NO: 1871 GGCAAAAGAGAACUUUAAGtt SEQ ID NO: 1872 AAGAGAACUUUAAGUUCCUtt SEQ ID NO: 1873 GAGAACUUUAAGUUCCUUGtt SEQ ID NO: 1874 CUUUAAGUUCCUUGUUCCAtt SEQ ID NO: 1875 GUUCCUUGUUCCAGCCCGGtt SEQ ID NO: 1876 AGAAAGAAAGGAAAGGUCAtt SEQ ID NO: 1877 AGAAAGGAAAGGUCACAGUtt SEQ ID NO: 1878 AGGAAAGGUCACAGUGACCtt SEQ ID NO: 1879 AGGUCACAGUGACCUAGGAtt SEQ ID NO: 1880 CCUUCCUGCCCUUUUGGCUtt SEQ ID NO: 1881 CAGCUGAGAAAUCUAUGAAtt SEQ ID NO: 1882 AUCUAUGAAGCUGAGAUUCtt SEQ ID NO: 1883 GCUGAGAUUCUGAAGGACCtt SEQ ID NO: 1884 GGACCCAGCUUAGGUUCUUtt SEQ ID NO: 1885 UUCCCUUCCUUUUCCAGGGtt SEQ ID NO: 1886 ACACACACAUUUCCCCCUUtt SEQ ID NO: 1887 GCCACUGGCCCCCCAUAGCtt SEQ ID NO: 1888 GUGGAAGAACUAGGAUGGCtt SEQ ID NO: 1889 GAACUAGGAUGGCUUUCCAtt SEQ ID NO: 1890 CUAGGAUGGCUUUCCAAAGtt SEQ ID NO: 1891 AGUCUUCUAGAAAUGAAGUtt SEQ ID NO: 1892 AUGAAGUUCUUUCUCUGUGtt SEQ ID NO: 1893 GUUCUUUCUCUGUGCAGCUtt SEQ ID NO: 1894 GAUGUUUCAUUAUCUUGGGtt SEQ ID NO: 1895 ACCACUUCCCCAGGCUUCUtt SEQ ID NO: 1896 CAGGAUUUGGCCUUAGCUUtt SEQ ID NO: 1897 GGGGGGGUGUUGUGGUUUUtt SEQ ID NO: 1898 AGCAUUUGCCUUUCUUCCUtt SEQ ID NO: 1899 CAUAACAAUCGUGGUAACAtt SEQ ID NO: 1900 CAAUCGUGGUAACAGAAUGtt SEQ ID NO: 1901 UCGUGGUAACAGAAUGCGAtt SEQ ID NO: 1902 CAGAAUGCGACUGCUGAUUtt SEQ ID NO: 1903 UGCGACUGCUGAUUUACCGtt SEQ ID NO: 1904 UGUAAGUAAAAAAAGGAAAtt SEQ ID NO: 1905 GUAAAAAAAGGAAAAAAAGtt SEQ ID NO: 1906 AAAAAGGAAAAAAAGAAAAtt SEQ ID NO: 1907 AAAGGAAAAAAAGAAAAAAtt SEQ ID NO: 1908 AGGAAAAAAAGAAAAAAAAtt SEQ ID NO: 1909 AAAAAGAAAAAAAAAAAAAtt SEQ ID NO: 1910 AAAGAAAAAAAAAAAAAAAtt SEQ ID NO: 1911 AGAAAAAAAAAAAAAAAAAtt SEQ ID NO: 1912 AAAAAAAAAAAAAAAAAAAtt

TABLE 9 Candidate siRNAs for RPS26, SEQ ID NOs: 1913-2002 are based on NM_001029. SEQ ID NO: 1913 UGGCGGAAGAAAAUCGAGGtt SEQ ID NO: 1914 AAAGUGCACAUGGGACUAUtt SEQ ID NO: 1915 AUGCGUUCCUAGUGUUUAUtt SEQ ID NO: 1916 GGAAAUGCGUUCCUAGUGUtt SEQ ID NO: 1917 AAUCUAGGGUGGAAAUGCGtt SEQ ID NO: 1918 AUUCCUUUACAUUCAGCAUtt SEQ ID NO: 1919 ACUCAAAUAUUCCUUUACAtt SEQ ID NO: 1920 ACUUUACUCAAAUAUUCCUtt SEQ ID NO: 1921 AACUCACUUUACUCAAAUAtt SEQ ID NO: 1922 UCAAGAACGGCAACUCACUtt SEQ ID NO: 1923 GAAUCCUUAGGAGACGGGCtt SEQ ID NO: 1924 GCGGACACCGGGAGAAUCCtt SEQ ID NO: 1925 CCUUCUUUUCUUUGUCAUCtt SEQ ID NO: 1926 CCAUUGUUCCUUCUUUUCUtt SEQ ID NO: 1927 ACGACCAUUGUUCCUUCUUtt SEQ ID NO: 1928 GCACGACCAUUGUUCCUUCtt SEQ ID NO: 1929 UUGGCACGACCAUUGUUCCtt SEQ ID NO: 1930 CUUUUUGGCACGACCAUUGtt SEQ ID NO: 1931 GCCCUUUUUGGCACGACCAtt SEQ ID NO: 1932 CACGUGGCCGCGGCCCUUUtt SEQ ID NO: 1933 UGCACGUGGCCGCGGCCCUtt SEQ ID NO: 1934 GGGCACGCAUCGGGCACAGtt SEQ ID NO: 1935 UUUCUUAAUGGCCUUGUCCtt SEQ ID NO: 1936 GACGAAUUUCUUAAUGGCCtt SEQ ID NO: 1937 GUUUCGAAUGACGAAUUUCtt SEQ ID NO: 1938 UAUGUUUCGAAUGACGAAUtt SEQ ID NO: 1939 GCUGCGGCCUCCACUAUGUtt SEQ ID NO: 1940 AGGCAUCGAAGACGCUCGCtt SEQ ID NO: 1941 AUGUAGCUUCACAUACAGCtt SEQ ID NO: 1942 ACUCACACAGUAAUGUAGCtt SEQ ID NO: 1943 CUGACUACUUUGCUGUGAAtt SEQ ID NO: 1944 AGAUCGAUUCCUGACUACUtt SEQ ID NO: 1945 GCGGGCUUCACGAGAUCGAtt SEQ ID NO: 1946 GUGUUCGGUCCUUGCGGGCtt SEQ ID NO: 1947 GGGUGGGGGUGUUCGGUCCtt SEQ ID NO: 1948 CUAAAUCGGGGUGGGGGUGtt SEQ ID NO: 1949 UCAGCUCCUUACAUGGGCUtt SEQ ID NO: 1950 UCUUUAAGAACUCAGCUCCtt SEQ ID NO: 1951 AAUAGCCUGUCUUCAGUCUtt SEQ ID NO: 1952 CUCCAGAGAAUAGCCUGUCtt SEQ ID NO: 1953 UACAAUUUCCAUUUUAUUUtt SEQ ID NO: 1954 AGUACAAUUUCCAUUUUAUtt SEQ ID NO: 1955 UUUAAGUACAAUUUCCAUUtt SEQ ID NO: 1956 UUUUUAAGUACAAUUUCCAtt SEQ ID NO: 1957 UUUUUUUUUUAAGUACAAUtt SEQ ID NO: 1958 CCUCGAUUUUCUUCCGCCAtt SEQ ID NO: 1959 AUAGUCCCAUGUGCACUUUtt SEQ ID NO: 1960 AUAAACACUAGGAACGCAUtt SEQ ID NO: 1961 ACACUAGGAACGCAUUUCCtt SEQ ID NO: 1962 CGCAUUUCCACCCUAGAUUtt SEQ ID NO: 1963 AUGCUGAAUGUAAAGGAAUtt SEQ ID NO: 1964 UGUAAAGGAAUAUUUGAGUtt SEQ ID NO: 1965 AGGAAUAUUUGAGUAAAGUtt SEQ ID NO: 1966 UAUUUGAGUAAAGUGAGUUtt SEQ ID NO: 1967 AGUGAGUUGCCGUUCUUGAtt SEQ ID NO: 1968 GCCCGUCUCCUAAGGAUUCtt SEQ ID NO: 1969 GGAUUCUCCCGGUGUCCGCtt SEQ ID NO: 1970 GAUGACAAAGAAAAGAAGGtt SEQ ID NO: 1971 AGAAAAGAAGGAACAAUGGtt SEQ ID NO: 1972 AAGAAGGAACAAUGGUCGUtt SEQ ID NO: 1973 GAAGGAACAAUGGUCGUGCtt SEQ ID NO: 1974 GGAACAAUGGUCGUGCCAAtt SEQ ID NO: 1975 CAAUGGUCGUGCCAAAAAGtt SEQ ID NO: 1976 UGGUCGUGCCAAAAAGGGCtt SEQ ID NO: 1977 AAAGGGCCGCGGCCACGUGtt SEQ ID NO: 1978 AGGGCCGCGGCCACGUGCAtt SEQ ID NO: 1979 CUGUGCCCGAUGCGUGCCCtt SEQ ID NO: 1980 GGACAAGGCCAUUAAGAAAtt SEQ ID NO: 1981 GGCCAUUAAGAAAUUCGUCtt SEQ ID NO: 1982 GAAAUUCGUCAUUCGAAACtt SEQ ID NO: 1983 AUUCGUCAUUCGAAACAUAtt SEQ ID NO: 1984 ACAUAGUGGAGGCCGCAGCtt SEQ ID NO: 1985 GCGAGCGUCUUCGAUGCCUtt SEQ ID NO: 1986 GCUGUAUGUGAAGCUACAUtt SEQ ID NO: 1987 GCUACAUUACUGUGUGAGUtt SEQ ID NO: 1988 UUCACAGCAAAGUAGUCAGtt SEQ ID NO: 1989 AGUAGUCAGGAAUCGAUCUtt SEQ ID NO: 1990 UCGAUCUCGUGAAGCCCGCtt SEQ ID NO: 1991 GCCCGCAAGGACCGAACACtt SEQ ID NO: 1992 GGACCGAACACCCCCACCCtt SEQ ID NO: 1993 CACCCCCACCCCGAUUUAGtt SEQ ID NO: 1994 AGCCCAUGUAAGGAGCUGAtt SEQ ID NO: 1995 GGAGCUGAGUUCUUAAAGAtt SEQ ID NO: 1996 AGACUGAAGACAGGCUAUUtt SEQ ID NO: 1997 GACAGGCUAUUCUCUGGAGtt SEQ ID NO: 1998 AAAUAAAAUGGAAAUUGUAtt SEQ ID NO: 1999 AUAAAAUGGAAAUUGUACUtt SEQ ID NO: 2000 AAUGGAAAUUGUACUUAAAtt SEQ ID NO: 2001 UGGAAAUUGUACUUAAAAAtt SEQ ID NO: 2002 AUUGUACUUAAAAAAAAAAtt

TABLE 10 Candidate siRNAs for SUOX, SEQ ID NOs: 2003-2204 are based on NM_000456, SEQ ID NOs: 2205-2394 are based on NM_001032386, and SEQ ID NOs: 2395-2576 are based on NM_001032387. SEQ ID NO: 2003 AGGGGCGGGGCCAGCGCCGtt SEQ ID NO: 2004 ACCAGCCCAGCUCUGCGAGtt SEQ ID NO: 2005 UGUCUUCAGCACUGCAAUUtt SEQ ID NO: 2006 AGUGUCUUCAGCACUGCAAtt SEQ ID NO: 2007 CUUUUGCGGGUCCAGUGUCtt SEQ ID NO: 2008 GUUUGGGAGGGACAGCCUUtt SEQ ID NO: 2009 AGGUUUGGGAGGGACAGCCtt SEQ ID NO: 2010 UGAGCCCAGAAUCCCAGGUtt SEQ ID NO: 2011 CUCAAUGCCAGCAGCCUGUtt SEQ ID NO: 2012 GACUGCUAGAGGCCAGGAGtt SEQ ID NO: 2013 UUCCGGACACACUAGCACUtt SEQ ID NO: 2014 GAGACCAAGAACCCACCAAtt SEQ ID NO: 2015 AGGGUCCGCGGCUUCAUUCtt SEQ ID NO: 2016 GCGAGGGUCCGCGGCUUCAtt SEQ ID NO: 2017 GACUGCGAGGGUCCGCGGCtt SEQ ID NO: 2018 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO: 2019 ACUUGAGUCUGCAGGCCUGtt SEQ ID NO: 2020 GAUCCUUGAGGGGAUUGACtt SEQ ID NO: 2021 AUGCAGAUCCUUGAGGGGAtt SEQ ID NO: 2022 CAGGCCUGAAUGCAGAUCCtt SEQ ID NO: 2023 UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2024 CCAUCCCUGGGUGCUGGAGtt SEQ ID NO: 2025 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2026 GUGGGAACUCACUUCCUCCtt SEQ ID NO: 2027 GGCUGGUGUGGGAACUCACtt SEQ ID NO: 2028 CUGGAUGUAGGUCCACAAAtt SEQ ID NO: 2029 CCAGCUGCUAGCAUCAGCUtt SEQ ID NO: 2030 CUCACGCACAUGGGACUGGtt SEQ ID NO: 2031 AGGAUUCAGCUCCCCAAUCtt SEQ ID NO: 2032 GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2033 CGGUGGGGGCUACCUUGUCtt SEQ ID NO: 2034 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2035 GGGCCGCUGGCUGUUGACCtt SEQ ID NO: 2036 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO: 2037 CUCAGGGGGAGGCUCUGCAtt SEQ ID NO: 2038 GGUUGGGUGUGAUGUAGUUtt SEQ ID NO: 2039 AGGGUUGGGUGUGAUGUAGtt SEQ ID NO: 2040 CCGGGUGAAGAAGAUAGGGtt SEQ ID NO: 2041 GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2042 AUAGGUGUCUGGAUCCAGGtt SEQ ID NO: 2043 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2044 AGUCAUCUCAGAGCGUCGGtt SEQ ID NO: 2045 CUCCAGACCUUUUACUUCUtt SEQ ID NO: 2046 UCCACUCCAGACCUUUUACtt SEQ ID NO: 2047 GUUCUCCACUCCAGACCUUtt SEQ ID NO: 2048 CUGUUCUCCACUCCAGACCtt SEQ ID NO: 2049 GCAGUGCUGAUGGCUCCUGtt SEQ ID NO: 2050 GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2051 AGCAGACGUGGGCCUCAGUtt SEQ ID NO: 2052 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2053 ACGUGGCAGAGGCUGCCCAtt SEQ ID NO: 2054 ACUCACUCUGCCCAGCCAUtt SEQ ID NO: 2055 GUUGCCAGUGGCUGUAACUtt SEQ ID NO: 2056 AGCCUUUGUAAUCCCGCCGtt SEQ ID NO: 2057 CACAGAUGGAGAGAAGCCUtt SEQ ID NO: 2058 UGGCCGACUGGACAGGAAGtt SEQ ID NO: 2059 UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2060 ACCACUCCAUGCAUAGCCCtt SEQ ID NO: 2061 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2062 CUGUUCCUCUCCAUCCAGCtt SEQ ID NO: 2063 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO: 2064 CAGACGCCAUGCCCAGGCCtt SEQ ID NO: 2065 UCCAGCUGGCACAGGGGCUtt SEQ ID NO: 2066 AAACAAUGUUCAGUUCCUUtt SEQ ID NO: 2067 ACAAACAAUGUUCAGUUCCtt SEQ ID NO: 2068 CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2069 CACAGCCUUACAAACAAUGtt SEQ ID NO: 2070 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2071 CACGGUGUCUGGCUGCACAtt SEQ ID NO: 2072 ACACCUCGCAGGUUCCAGAtt SEQ ID NO: 2073 GCUGAGAACACCUCGCAGGtt SEQ ID NO: 2074 AUGGACACGAUGCCAGGCAtt SEQ ID NO: 2075 AGGGGUGGAGGUGGCUCCUtt SEQ ID NO: 2076 UGAAAGGUGGGAAAGAUUUtt SEQ ID NO: 2077 GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2078 AGAGUUGUGAUCCAAGAAGtt SEQ ID NO: 2079 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2080 AUGUGUACUUGGGUAUGGCtt SEQ ID NO: 2081 AAAUGUGCUAUAUGUGUACtt SEQ ID NO: 2082 GUCCAAAGAGGGAAGGUCCtt SEQ ID NO: 2083 UCACACUUCCUGGCACAGGtt SEQ ID NO: 2084 UUGCUGUAACAGCUCACACtt SEQ ID NO: 2085 UUUUUUCACUUCUAGCCCCtt SEQ ID NO: 2086 CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2087 UGUCUCCAGAAUUACUUUUtt SEQ ID NO: 2088 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2089 UGCUUGUCUCCAGAAUUACtt SEQ ID NO: 2090 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO: 2091 UAGGAAGAGAAAAUAGUGCtt SEQ ID NO: 2092 GCCUUGAUGGCAGUAGGCAtt SEQ ID NO: 2093 AGAAAAGCAAAACAAGGCCtt SEQ ID NO: 2094 UUACACAUGCCACACACAUtt SEQ ID NO: 2095 GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2096 UAAGAUAGUAUAUACACUUtt SEQ ID NO: 2097 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2098 AGGGAGACGGUUGUGCCCCtt SEQ ID NO: 2099 GAACUAUAAAGGGAGACGGtt SEQ ID NO: 2100 AUCUUAAACAGACUAUUUAtt SEQ ID NO: 2101 AUGAUCUUAAACAGACUAUtt SEQ ID NO: 2102 UUUUUUUUUUUUUAUGAUCtt SEQ ID NO: 2103 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 2104 CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2105 CUCGCAGAGCUGGGCUGGUtt SEQ ID NO: 2106 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2107 UUGCAGUGCUGAAGACACUtt SEQ ID NO: 2108 GACACUGGACCCGCAAAAGtt SEQ ID NO: 2109 AAGGCUGUCCCUCCCAAACtt SEQ ID NO: 2110 GGCUGUCCCUCCCAAACCUtt SEQ ID NO: 2111 ACCUGGGAUUCUGGGCUCAtt SEQ ID NO: 2112 ACAGGCUGCUGGCAUUGAGtt SEQ ID NO: 2113 CUCCUGGCCUCUAGCAGUCtt SEQ ID NO: 2114 AGUGCUAGUGUGUCCGGAAtt SEQ ID NO: 2115 UUGGUGGGUUCUUGGUCUCtt SEQ ID NO: 2116 GAAUGAAGCCGCGGACCCUtt SEQ ID NO: 2117 UGAAGCCGCGGACCCUCGCtt SEQ ID NO: 2118 GCCGCGGACCCUCGCAGUCtt SEQ ID NO: 2119 UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2120 CAGGCCUGCAGACUCAAGUtt SEQ ID NO: 2121 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO: 2122 UCCCCUCAAGGAUCUGCAUtt SEQ ID NO: 2123 GGAUCUGCAUUCAGGCCUGtt SEQ ID NO: 2124 AUGAUUCAUUUCAGCCCCAtt SEQ ID NO: 2125 CUCCAGCACCCAGGGAUGGtt SEQ ID NO: 2126 CACACAUAUACACUAAGGAtt SEQ ID NO: 2127 GGAGGAAGUGAGUUCCCACtt SEQ ID NO: 2128 GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2129 UUUGUGGACCUACAUCCAGtt SEQ ID NO: 2130 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO: 2131 CCAGUCCCAUGUGCGUGAGtt SEQ ID NO: 2132 GAUUGGGGAGCUGAAUCCUtt SEQ ID NO: 2133 UCCUGAAGACAAGGUAGCCtt SEQ ID NO: 2134 GACAAGGUAGCCCCCACCGtt SEQ ID NO: 2135 GGUAGCCCCCACCGUGGAGtt SEQ ID NO: 2136 GGUCAACAGCCAGCGGCCCtt SEQ ID NO: 2137 CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2138 UGCAGAGCCUCCCCCUGAGtt SEQ ID NO: 2139 AACUACAUCACACCCAACCtt SEQ ID NO: 2140 CUACAUCACACCCAACCCUtt SEQ ID NO: 2141 CCCUAUCUUCUUCACCCGGtt SEQ ID NO: 2142 CCAUCUGCCUGUACCUAACtt SEQ ID NO: 2143 CCUGGAUCCAGACACCUAUtt SEQ ID NO: 2144 CUUUCCCAGGUACGAGAUCtt SEQ ID NO: 2145 CCGACGCUCUGAGAUGACUtt SEQ ID NO: 2146 AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2147 GUAAAAGGUCUGGAGUGGAtt SEQ ID NO: 2148 AAGGUCUGGAGUGGAGAACtt SEQ ID NO: 2149 GGUCUGGAGUGGAGAACAGtt SEQ ID NO: 2150 CAGGAGCCAUCAGCACUGCtt SEQ ID NO: 2151 CUCUGUGAAACUGAGGCCCtt SEQ ID NO: 2152 ACUGAGGCCCACGUCUGCUtt SEQ ID NO: 2153 GCUGAGGUCCUGCUGGCAUtt SEQ ID NO: 2154 UGGGCAGCCUCUGCCACGUtt SEQ ID NO: 2155 AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2156 AGUUACAGCCACUGGCAACtt SEQ ID NO: 2157 CGGCGGGAUUACAAAGGCUtt SEQ ID NO: 2158 AGGCUUCUCUCCAUCUGUGtt SEQ ID NO: 2159 CUUCCUGUCCAGUCGGCCAtt SEQ ID NO: 2160 UCAGGGGAGGUGACCAUCAtt SEQ ID NO: 2161 GGGCUAUGCAUGGAGUGGUtt SEQ ID NO: 2162 CCUGGCAGGUGGCUAAGCUtt SEQ ID NO: 2163 GCUGGAUGGAGAGGAACAGtt SEQ ID NO: 2164 CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2165 GGCCUGGGCAUGGCGUCUGtt SEQ ID NO: 2166 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO: 2167 AAGGAACUGAACAUUGUUUtt SEQ ID NO: 2168 GGAACUGAACAUUGUUUGUtt SEQ ID NO: 2169 CUGAACAUUGUUUGUAAGGtt SEQ ID NO: 2170 CAUUGUUUGUAAGGCUGUGtt SEQ ID NO: 2171 GGCUGUGGAUGAUGGUUACtt SEQ ID NO: 2172 UGUGCAGCCAGACACCGUGtt SEQ ID NO: 2173 UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2174 CCUGCGAGGUGUUCUCAGCtt SEQ ID NO: 2175 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO: 2176 AGGAGCCACCUCCACCCCUtt SEQ ID NO: 2177 AAAUCUUUCCCACCUUUCAtt SEQ ID NO: 2178 AUCUUUCCCACCUUUCAACtt SEQ ID NO: 2179 CUUCUUGGAUCACAACUCUtt SEQ ID NO: 2180 CUCUGGCCUUCCUAAGCCAtt SEQ ID NO: 2181 GCCAUACCCAAGUACACAUtt SEQ ID NO: 2182 GUACACAUAUAGCACAUUUtt SEQ ID NO: 2183 GGACCUUCCCUCUUUGGACtt SEQ ID NO: 2184 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO: 2185 GUGUGAGCUGUUACAGCAAtt SEQ ID NO: 2186 GGGGCUAGAAGUGAAAAAAtt SEQ ID NO: 2187 GUGAAAAAAGUAAUUCUGGtt SEQ ID NO: 2188 AAAAGUAAUUCUGGAGACAtt SEQ ID NO: 2189 AAGUAAUUCUGGAGACAAGtt SEQ ID NO: 2190 GUAAUUCUGGAGACAAGCAtt SEQ ID NO: 2191 UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2192 GCACUAUUUUCUCUUCCUAtt SEQ ID NO: 2193 UGCCUACUGCCAUCAAGGCtt SEQ ID NO: 2194 GGCCUUGUUUUGCUUUUCUtt SEQ ID NO: 2195 AUGUGUGUGGCAUGUGUAAtt SEQ ID NO: 2196 GAAAAGUGUAUAUACUAUCtt SEQ ID NO: 2197 AAGUGUAUAUACUAUCUUAtt SEQ ID NO: 2198 GUGUAUAUACUAUCUUAUAtt SEQ ID NO: 2199 GGGGCACAACCGUCUCCCUtt SEQ ID NO: 2200 CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2201 UAAAUAGUCUGUUUAAGAUtt SEQ ID NO: 2202 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO: 2203 GAUCAUAAAAAAAAAAAAAtt SEQ ID NO: 2204 AAAAAAAAAAAAAAAAAAAtt SEQ ID NO: 2205 AGGGGCGGGGCCAGCGCCGtt SEQ ID NO: 2206 ACCAGCCCAGCUCUGCGAGtt SEQ ID NO: 2207 UGUCUUCAGCACUGCAAUUtt SEQ ID NO: 2208 AGUGUCUUCAGCACUGCAAtt SEQ ID NO: 2209 CUUUUGCGGGUCCAGUGUCtt SEQ ID NO: 2210 GUUUGGGAGGGACAGCCUUtt SEQ ID NO: 2211 AGGUUUGGGAGGGACAGCCtt SEQ ID NO: 2212 UGAGCCCAGAAUCCCAGGUtt SEQ ID NO: 2213 CUCAAUGCCAGCAGCCUGUtt SEQ ID NO: 2214 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO: 2215 ACUUGAGUCUGCAGGCCUGtt SEQ ID NO: 2216 GAUCCUUGAGGGGAUUGACtt SEQ ID NO: 2217 AUGCAGAUCCUUGAGGGGAtt SEQ ID NO: 2218 CAGGCCUGAAUGCAGAUCCtt SEQ ID NO: 2219 UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2220 CCAUCCCUGGGUGCUGGAGtt SEQ ID NO: 2221 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2222 GUGGGAACUCACUUCCUCCtt SEQ ID NO: 2223 GGCUGGUGUGGGAACUCACtt SEQ ID NO: 2224 CUGGAUGUAGGUCCACAAAtt SEQ ID NO: 2225 CCAGCUGCUAGCAUCAGCUtt SEQ ID NO: 2226 CUCACGCACAUGGGACUGGtt SEQ ID NO: 2227 AGGAUUCAGCUCCCCAAUCtt SEQ ID NO: 2228 GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2229 CGGUGGGGGCUACCUUGUCtt SEQ ID NO: 2230 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2231 GGGCCGCUGGCUGUUGACCtt SEQ ID NO: 2232 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO: 2233 CUCAGGGGGAGGCUCUGCAtt SEQ ID NO: 2234 GGUUGGGUGUGAUGUAGUUtt SEQ ID NO: 2235 AGGGUUGGGUGUGAUGUAGtt SEQ ID NO: 2236 CCGGGUGAAGAAGAUAGGGtt SEQ ID NO: 2237 GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2238 AUAGGUGUCUGGAUCCAGGtt SEQ ID NO: 2239 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2240 AGUCAUCUCAGAGCGUCGGtt SEQ ID NO: 2241 CUCCAGACCUUUUACUUCUtt SEQ ID NO: 2242 UCCACUCCAGACCUUUUACtt SEQ ID NO: 2243 GUUCUCCACUCCAGACCUUtt SEQ ID NO: 2244 CUGUUCUCCACUCCAGACCtt SEQ ID NO: 2245 GCAGUGCUGAUGGCUCCUGtt SEQ ID NO: 2246 GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2247 AGCAGACGUGGGCCUCAGUtt SEQ ID NO: 2248 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2249 ACGUGGCAGAGGCUGCCCAtt SEQ ID NO: 2250 ACUCACUCUGCCCAGCCAUtt SEQ ID NO: 2251 GUUGCCAGUGGCUGUAACUtt SEQ ID NO: 2252 AGCCUUUGUAAUCCCGCCGtt SEQ ID NO: 2253 CACAGAUGGAGAGAAGCCUtt SEQ ID NO: 2254 UGGCCGACUGGACAGGAAGtt SEQ ID NO: 2255 UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2256 ACCACUCCAUGCAUAGCCCtt SEQ ID NO: 2257 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2258 CUGUUCCUCUCCAUCCAGCtt SEQ ID NO: 2259 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO: 2260 CAGACGCCAUGCCCAGGCCtt SEQ ID NO: 2261 UCCAGCUGGCACAGGGGCUtt SEQ ID NO: 2262 AAACAAUGUUCAGUUCCUUtt SEQ ID NO: 2263 ACAAACAAUGUUCAGUUCCtt SEQ ID NO: 2264 CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2265 CACAGCCUUACAAACAAUGtt SEQ ID NO: 2266 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2267 CACGGUGUCUGGCUGCACAtt SEQ ID NO: 2268 ACACCUCGCAGGUUCCAGAtt SEQ ID NO: 2269 GCUGAGAACACCUCGCAGGtt SEQ ID NO: 2270 AUGGACACGAUGCCAGGCAtt SEQ ID NO: 2271 AGGGGUGGAGGUGGCUCCUtt SEQ ID NO: 2272 UGAAAGGUGGGAAAGAUUUtt SEQ ID NO: 2273 GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2274 AGAGUUGUGAUCCAAGAAGtt SEQ ID NO: 2275 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2276 AUGUGUACUUGGGUAUGGCtt SEQ ID NO: 2277 AAAUGUGCUAUAUGUGUACtt SEQ ID NO: 2278 GUCCAAAGAGGGAAGGUCCtt SEQ ID NO: 2279 UCACACUUCCUGGCACAGGtt SEQ ID NO: 2280 UUGCUGUAACAGCUCACACtt SEQ ID NO: 2281 UUUUUUCACUUCUAGCCCCtt SEQ ID NO: 2282 CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2283 UGUCUCCAGAAUUACUUUUtt SEQ ID NO: 2284 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2285 UGCUUGUCUCCAGAAUUACtt SEQ ID NO: 2286 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO: 2287 UAGGAAGAGAAAAUAGUGCtt SEQ ID NO: 2288 GCCUUGAUGGCAGUAGGCAtt SEQ ID NO: 2289 AGAAAAGCAAAACAAGGCCtt SEQ ID NO: 2290 UUACACAUGCCACACACAUtt SEQ ID NO: 2291 GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2292 UAAGAUAGUAUAUACACUUtt SEQ ID NO: 2293 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2294 AGGGAGACGGUUGUGCCCCtt SEQ ID NO: 2295 GAACUAUAAAGGGAGACGGtt SEQ ID NO: 2296 AUCUUAAACAGACUAUUUAtt SEQ ID NO: 2297 AUGAUCUUAAACAGACUAUtt SEQ ID NO: 2298 UUUUUUUUUUUUUAUGAUCtt SEQ ID NO: 2299 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 2300 CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2301 CUCGCAGAGCUGGGCUGGUtt SEQ ID NO: 2302 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2303 UUGCAGUGCUGAAGACACUtt SEQ ID NO: 2304 GACACUGGACCCGCAAAAGtt SEQ ID NO: 2305 AAGGCUGUCCCUCCCAAACtt SEQ ID NO: 2306 GGCUGUCCCUCCCAAACCUtt SEQ ID NO: 2307 ACCUGGGAUUCUGGGCUCAtt SEQ ID NO: 2308 ACAGGCUGCUGGCAUUGAGtt SEQ ID NO: 2309 UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2310 CAGGCCUGCAGACUCAAGUtt SEQ ID NO: 2311 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO: 2312 UCCCCUCAAGGAUCUGCAUtt SEQ ID NO: 2313 GGAUCUGCAUUCAGGCCUGtt SEQ ID NO: 2314 AUGAUUCAUUUCAGCCCCAtt SEQ ID NO: 2315 CUCCAGCACCCAGGGAUGGtt SEQ ID NO: 2316 CACACAUAUACACUAAGGAtt SEQ ID NO: 2317 GGAGGAAGUGAGUUCCCACtt SEQ ID NO: 2318 GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2319 UUUGUGGACCUACAUCCAGtt SEQ ID NO: 2320 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO: 2321 CCAGUCCCAUGUGCGUGAGtt SEQ ID NO: 2322 GAUUGGGGAGCUGAAUCCUtt SEQ ID NO: 2323 UCCUGAAGACAAGGUAGCCtt SEQ ID NO: 2324 GACAAGGUAGCCCCCACCGtt SEQ ID NO: 2325 GGUAGCCCCCACCGUGGAGtt SEQ ID NO: 2326 GGUCAACAGCCAGCGGCCCtt SEQ ID NO: 2327 CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2328 UGCAGAGCCUCCCCCUGAGtt SEQ ID NO: 2329 AACUACAUCACACCCAACCtt SEQ ID NO: 2330 CUACAUCACACCCAACCCUtt SEQ ID NO: 2331 CCCUAUCUUCUUCACCCGGtt SEQ ID NO: 2332 CCAUCUGCCUGUACCUAACtt SEQ ID NO: 2333 CCUGGAUCCAGACACCUAUtt SEQ ID NO: 2334 CUUUCCCAGGUACGAGAUCtt SEQ ID NO: 2335 CCGACGCUCUGAGAUGACUtt SEQ ID NO: 2336 AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2337 GUAAAAGGUCUGGAGUGGAtt SEQ ID NO: 2338 AAGGUCUGGAGUGGAGAACtt SEQ ID NO: 2339 GGUCUGGAGUGGAGAACAGtt SEQ ID NO: 2340 CAGGAGCCAUCAGCACUGCtt SEQ ID NO: 2341 CUCUGUGAAACUGAGGCCCtt SEQ ID NO: 2342 ACUGAGGCCCACGUCUGCUtt SEQ ID NO: 2343 GCUGAGGUCCUGCUGGCAUtt SEQ ID NO: 2344 UGGGCAGCCUCUGCCACGUtt SEQ ID NO: 2345 AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2346 AGUUACAGCCACUGGCAACtt SEQ ID NO: 2347 CGGCGGGAUUACAAAGGCUtt SEQ ID NO: 2348 AGGCUUCUCUCCAUCUGUGtt SEQ ID NO: 2349 CUUCCUGUCCAGUCGGCCAtt SEQ ID NO: 2350 UCAGGGGAGGUGACCAUCAtt SEQ ID NO: 2351 GGGCUAUGCAUGGAGUGGUtt SEQ ID NO: 2352 CCUGGCAGGUGGCUAAGCUtt SEQ ID NO: 2353 GCUGGAUGGAGAGGAACAGtt SEQ ID NO: 2354 CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2355 GGCCUGGGCAUGGCGUCUGtt SEQ ID NO: 2356 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO: 2357 AAGGAACUGAACAUUGUUUtt SEQ ID NO: 2358 GGAACUGAACAUUGUUUGUtt SEQ ID NO: 2359 CUGAACAUUGUUUGUAAGGtt SEQ ID NO: 2360 CAUUGUUUGUAAGGCUGUGtt SEQ ID NO: 2361 GGCUGUGGAUGAUGGUUACtt SEQ ID NO: 2362 UGUGCAGCCAGACACCGUGtt SEQ ID NO: 2363 UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2364 CCUGCGAGGUGUUCUCAGCtt SEQ ID NO: 2365 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO: 2366 AGGAGCCACCUCCACCCCUtt SEQ ID NO: 2367 AAAUCUUUCCCACCUUUCAtt SEQ ID NO: 2368 AUCUUUCCCACCUUUCAACtt SEQ ID NO: 2369 CUUCUUGGAUCACAACUCUtt SEQ ID NO: 2370 CUCUGGCCUUCCUAAGCCAtt SEQ ID NO: 2371 GCCAUACCCAAGUACACAUtt SEQ ID NO: 2372 GUACACAUAUAGCACAUUUtt SEQ ID NO: 2373 GGACCUUCCCUCUUUGGACtt SEQ ID NO: 2374 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO: 2375 GUGUGAGCUGUUACAGCAAtt SEQ ID NO: 2376 GGGGCUAGAAGUGAAAAAAtt SEQ ID NO: 2377 GUGAAAAAAGUAAUUCUGGtt SEQ ID NO: 2378 AAAAGUAAUUCUGGAGACAtt SEQ ID NO: 2379 AAGUAAUUCUGGAGACAAGtt SEQ ID NO: 2380 GUAAUUCUGGAGACAAGCAtt SEQ ID NO: 2381 UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2382 GCACUAUUUUCUCUUCCUAtt SEQ ID NO: 2383 UGCCUACUGCCAUCAAGGCtt SEQ ID NO: 2384 GGCCUUGUUUUGCUUUUCUtt SEQ ID NO: 2385 AUGUGUGUGGCAUGUGUAAtt SEQ ID NO: 2386 GAAAAGUGUAUAUACUAUCtt SEQ ID NO: 2387 AAGUGUAUAUACUAUCUUAtt SEQ ID NO: 2388 GUGUAUAUACUAUCUUAUAtt SEQ ID NO: 2389 GGGGCACAACCGUCUCCCUtt SEQ ID NO: 2390 CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2391 UAAAUAGUCUGUUUAAGAUtt SEQ ID NO: 2392 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO: 2393 GAUCAUAAAAAAAAAAAAAtt SEQ ID NO: 2394 AAAAAAAAAAAAAAAAAAAtt SEQ ID NO: 2395 AGGGGCGGGGCCAGCGCCGtt SEQ ID NO: 2396 ACCAGCCCAGCUCUGCGAGtt SEQ ID NO: 2397 UGUCUUCAGCACUGCAAUUtt SEQ ID NO: 2398 AGUGUCUUCAGCACUGCAAtt SEQ ID NO: 2399 GCAGACCGGGUCCAGUGUCtt SEQ ID NO: 2400 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO: 2401 ACUUGAGUCUGCAGGCCUGtt SEQ ID NO: 2402 GAUCCUUGAGGGGAUUGACtt SEQ ID NO: 2403 AUGCAGAUCCUUGAGGGGAtt SEQ ID NO: 2404 CAGGCCUGAAUGCAGAUCCtt SEQ ID NO: 2405 UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2406 CCAUCCCUGGGUGCUGGAGtt SEQ ID NO: 2407 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2408 GUGGGAACUCACUUCCUCCtt SEQ ID NO: 2409 GGCUGGUGUGGGAACUCACtt SEQ ID NO: 2410 CUGGAUGUAGGUCCACAAAtt SEQ ID NO: 2411 CCAGCUGCUAGCAUCAGCUtt SEQ ID NO: 2412 CUCACGCACAUGGGACUGGtt SEQ ID NO: 2413 AGGAUUCAGCUCCCCAAUCtt SEQ ID NO: 2414 GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2415 CGGUGGGGGCUACCUUGUCtt SEQ ID NO: 2416 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2417 GGGCCGCUGGCUGUUGACCtt SEQ ID NO: 2418 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO: 2419 CUCAGGGGGAGGCUCUGCAtt SEQ ID NO: 2420 GGUUGGGUGUGAUGUAGUUtt SEQ ID NO: 2421 AGGGUUGGGUGUGAUGUAGtt SEQ ID NO: 2422 CCGGGUGAAGAAGAUAGGGtt SEQ ID NO: 2423 GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2424 AUAGGUGUCUGGAUCCAGGtt SEQ ID NO: 2425 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2426 AGUCAUCUCAGAGCGUCGGtt SEQ ID NO: 2427 CUCCAGACCUUUUACUUCUtt SEQ ID NO: 2428 UCCACUCCAGACCUUUUACtt SEQ ID NO: 2429 GUUCUCCACUCCAGACCUUtt SEQ ID NO: 2430 CUGUUCUCCACUCCAGACCtt SEQ ID NO: 2431 GCAGUGCUGAUGGCUCCUGtt SEQ ID NO: 2432 GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2433 AGCAGACGUGGGCCUCAGUtt SEQ ID NO: 2434 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2435 ACGUGGCAGAGGCUGCCCAtt SEQ ID NO: 2436 ACUCACUCUGCCCAGCCAUtt SEQ ID NO: 2437 GUUGCCAGUGGCUGUAACUtt SEQ ID NO: 2438 AGCCUUUGUAAUCCCGCCGtt SEQ ID NO: 2439 CACAGAUGGAGAGAAGCCUtt SEQ ID NO: 2440 UGGCCGACUGGACAGGAAGtt SEQ ID NO: 2441 UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2442 ACCACUCCAUGCAUAGCCCtt SEQ ID NO: 2443 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2444 CUGUUCCUCUCCAUCCAGCtt SEQ ID NO: 2445 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO: 2446 CAGACGCCAUGCCCAGGCCtt SEQ ID NO: 2447 UCCAGCUGGCACAGGGGCUtt SEQ ID NO: 2448 AAACAAUGUUCAGUUCCUUtt SEQ ID NO: 2449 ACAAACAAUGUUCAGUUCCtt SEQ ID NO: 2450 CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2451 CACAGCCUUACAAACAAUGtt SEQ ID NO: 2452 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2453 CACGGUGUCUGGCUGCACAtt SEQ ID NO: 2454 ACACCUCGCAGGUUCCAGAtt SEQ ID NO: 2455 GCUGAGAACACCUCGCAGGtt SEQ ID NO: 2456 AUGGACACGAUGCCAGGCAtt SEQ ID NO: 2457 AGGGGUGGAGGUGGCUCCUtt SEQ ID NO: 2458 UGAAAGGUGGGAAAGAUUUtt SEQ ID NO: 2459 GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2460 AGAGUUGUGAUCCAAGAAGtt SEQ ID NO: 2461 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2462 AUGUGUACUUGGGUAUGGCtt SEQ ID NO: 2463 AAAUGUGCUAUAUGUGUACtt SEQ ID NO: 2464 GUCCAAAGAGGGAAGGUCCtt SEQ ID NO: 2465 UCACACUUCCUGGCACAGGtt SEQ ID NO: 2466 UUGCUGUAACAGCUCACACtt SEQ ID NO: 2467 UUUUUUCACUUCUAGCCCCtt SEQ ID NO: 2468 CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2469 UGUCUCCAGAAUUACUUUUtt SEQ ID NO: 2470 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2471 UGCUUGUCUCCAGAAUUACtt SEQ ID NO: 2472 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO: 2473 UAGGAAGAGAAAAUAGUGCtt SEQ ID NO: 2474 GCCUUGAUGGCAGUAGGCAtt SEQ ID NO: 2475 AGAAAAGCAAAACAAGGCCtt SEQ ID NO: 2476 UUACACAUGCCACACACAUtt SEQ ID NO: 2477 GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2478 UAAGAUAGUAUAUACACUUtt SEQ ID NO: 2479 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2480 AGGGAGACGGUUGUGCCCCtt SEQ ID NO: 2481 GAACUAUAAAGGGAGACGGtt SEQ ID NO: 2482 AUCUUAAACAGACUAUUUAtt SEQ ID NO: 2483 AUGAUCUUAAACAGACUAUtt SEQ ID NO: 2484 UUUUUUUUUUUUUAUGAUCtt SEQ ID NO: 2485 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 2486 CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2487 CUCGCAGAGCUGGGCUGGUtt SEQ ID NO: 2488 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2489 UUGCAGUGCUGAAGACACUtt SEQ ID NO: 2490 GACACUGGACCCGGUCUGCtt SEQ ID NO: 2491 UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2492 CAGGCCUGCAGACUCAAGUtt SEQ ID NO: 2493 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO: 2494 UCCCCUCAAGGAUCUGCAUtt SEQ ID NO: 2495 GGAUCUGCAUUCAGGCCUGtt SEQ ID NO: 2496 AUGAUUCAUUUCAGCCCCAtt SEQ ID NO: 2497 CUCCAGCACCCAGGGAUGGtt SEQ ID NO: 2498 CACACAUAUACACUAAGGAtt SEQ ID NO: 2499 GGAGGAAGUGAGUUCCCACtt SEQ ID NO: 2500 GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2501 UUUGUGGACCUACAUCCAGtt SEQ ID NO: 2502 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO: 2503 CCAGUCCCAUGUGCGUGAGtt SEQ ID NO: 2504 GAUUGGGGAGCUGAAUCCUtt SEQ ID NO: 2505 UCCUGAAGACAAGGUAGCCtt SEQ ID NO: 2506 GACAAGGUAGCCCCCACCGtt SEQ ID NO: 2507 GGUAGCCCCCACCGUGGAGtt SEQ ID NO: 2508 GGUCAACAGCCAGCGGCCCtt SEQ ID NO: 2509 CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2510 UGCAGAGCCUCCCCCUGAGtt SEQ ID NO: 2511 AACUACAUCACACCCAACCtt SEQ ID NO: 2512 CUACAUCACACCCAACCCUtt SEQ ID NO: 2513 CCCUAUCUUCUUCACCCGGtt SEQ ID NO: 2514 CCAUCUGCCUGUACCUAACtt SEQ ID NO: 2515 CCUGGAUCCAGACACCUAUtt SEQ ID NO: 2516 CUUUCCCAGGUACGAGAUCtt SEQ ID NO: 2517 CCGACGCUCUGAGAUGACUtt SEQ ID NO: 2518 AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2519 GUAAAAGGUCUGGAGUGGAtt SEQ ID NO: 2520 AAGGUCUGGAGUGGAGAACtt SEQ ID NO: 2521 GGUCUGGAGUGGAGAACAGtt SEQ ID NO: 2522 CAGGAGCCAUCAGCACUGCtt SEQ ID NO: 2523 CUCUGUGAAACUGAGGCCCtt SEQ ID NO: 2524 ACUGAGGCCCACGUCUGCUtt SEQ ID NO: 2525 GCUGAGGUCCUGCUGGCAUtt SEQ ID NO: 2526 UGGGCAGCCUCUGCCACGUtt SEQ ID NO: 2527 AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2528 AGUUACAGCCACUGGCAACtt SEQ ID NO: 2529 CGGCGGGAUUACAAAGGCUtt SEQ ID NO: 2530 AGGCUUCUCUCCAUCUGUGtt SEQ ID NO: 2531 CUUCCUGUCCAGUCGGCCAtt SEQ ID NO: 2532 UCAGGGGAGGUGACCAUCAtt SEQ ID NO: 2533 GGGCUAUGCAUGGAGUGGUtt SEQ ID NO: 2534 CCUGGCAGGUGGCUAAGCUtt SEQ ID NO: 2535 GCUGGAUGGAGAGGAACAGtt SEQ ID NO: 2536 CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2537 GGCCUGGGCAUGGCGUCUGtt SEQ ID NO: 2538 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO: 2539 AAGGAACUGAACAUUGUUUtt SEQ ID NO: 2540 GGAACUGAACAUUGUUUGUtt SEQ ID NO: 2541 CUGAACAUUGUUUGUAAGGtt SEQ ID NO: 2542 CAUUGUUUGUAAGGCUGUGtt SEQ ID NO: 2543 GGCUGUGGAUGAUGGUUACtt SEQ ID NO: 2544 UGUGCAGCCAGACACCGUGtt SEQ ID NO: 2545 UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2546 CCUGCGAGGUGUUCUCAGCtt SEQ ID NO: 2547 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO: 2548 AGGAGCCACCUCCACCCCUtt SEQ ID NO: 2549 AAAUCUUUCCCACCUUUCAtt SEQ ID NO: 2550 AUCUUUCCCACCUUUCAACtt SEQ ID NO: 2551 CUUCUUGGAUCACAACUCUtt SEQ ID NO: 2552 CUCUGGCCUUCCUAAGCCAtt SEQ ID NO: 2553 GCCAUACCCAAGUACACAUtt SEQ ID NO: 2554 GUACACAUAUAGCACAUUUtt SEQ ID NO: 2555 GGACCUUCCCUCUUUGGACtt SEQ ID NO: 2556 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO: 2557 GUGUGAGCUGUUACAGCAAtt SEQ ID NO: 2558 GGGGCUAGAAGUGAAAAAAtt SEQ ID NO: 2559 GUGAAAAAAGUAAUUCUGGtt SEQ ID NO: 2560 AAAAGUAAUUCUGGAGACAtt SEQ ID NO: 2561 AAGUAAUUCUGGAGACAAGtt SEQ ID NO: 2562 GUAAUUCUGGAGACAAGCAtt SEQ ID NO: 2563 UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2564 GCACUAUUUUCUCUUCCUAtt SEQ ID NO: 2565 UGCCUACUGCCAUCAAGGCtt SEQ ID NO: 2566 GGCCUUGUUUUGCUUUUCUtt SEQ ID NO: 2567 AUGUGUGUGGCAUGUGUAAtt SEQ ID NO: 2568 GAAAAGUGUAUAUACUAUCtt SEQ ID NO: 2569 AAGUGUAUAUACUAUCUUAtt SEQ ID NO: 2570 GUGUAUAUACUAUCUUAUAtt SEQ ID NO: 2571 GGGGCACAACCGUCUCCCUtt SEQ ID NO: 2572 CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2573 UAAAUAGUCUGUUUAAGAUtt SEQ ID NO: 2574 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO: 2575 GAUCAUAAAAAAAAAAAAAtt SEQ ID NO: 2576 AAAAAAAAAAAAAAAAAAAtt

Example III

The information herein above can be applied clinically to patients for diagnosing an increased susceptibility for developing T1D, and therapeutic intervention. A preferred embodiment of the invention comprises clinical application of the information described herein to a patient. Diagnostic compositions, including microarrays, and methods can be designed to identify the genetic alterations described herein in nucleic acids from a patient to assess susceptibility for developing T1D. This can occur after a patient arrives in the clinic; the patient has blood drawn, and using the diagnostic methods described herein, a clinician can detect a SNP in chromosome 12. The typical age range for a patient to be screened is between 9 and 12 years of age. The information obtained from the patient sample, which can optionally be amplified prior to assessment, will be used to diagnose a patient with an increased or decreased susceptibility for developing T1D. Kits for performing the diagnostic method of the invention are also provided herein. Such kits comprise a microarray comprising at least one of the SNPs provided herein in and the necessary reagents for assessing the patient samples as described above.

The identity of T1D-involved genes and the patient results will indicate which variants are present, and will identify those that possess an altered risk for developing T1D. The information provided herein allows for therapeutic intervention at earlier times in disease progression that previously possible. Also, as described herein above, RPS26 and other genes described on chromosome 12, provide a novel target for the development of new therapeutic agents efficacious for the treatment of T1D. In particular, it would be desirable to block expression of RPS26 in those patients that are more prone to develop the disease. In this regard, the therapeutic siRNAs described herein can be used to block expression of the gene product based on the patient signal, thereby inhibiting the pancreatic β-cell destruction that occurs in T1D.

REFERENCES

-   1. Cucca F, Lampis R, Congia M, et al. A correlation between the     relative predisposition of MHC class II alleles to type 1 diabetes     and the structure of their proteins. Human molecular genetics 2001;     10(19):2025-37. -   2. Julier C, Hyer R N, Davies J, et al. Insulin-IGF2 region on     chromosome 11p encodes a gene implicated in HLA-DR4-dependent     diabetes susceptibility. Nature 1991; 354(6349):155-9. -   3. Barratt B J, Payne F, Lowe C E, et al. Remapping the insulin     gene/IDDM2 locus in type 1 diabetes. Diabetes 2004; 53(7):1884-9. -   4. Bell G I, Horita S, Karam J H. A polymorphic locus near the human     insulin gene is associated with insulin-dependent diabetes mellitus.     Diabetes 1984; 33(2):176-83. -   5. Bottini N, Musumeci L, Alonso A, et al. A functional variant of     lymphoid tyrosine phosphatase is associated with type I diabetes.     Nature genetics 2004; 36(4):337-8. -   6. Smyth D, Cooper J D, Collins J E, et al. Replication of an     association between the lymphoid tyrosine phosphatase locus     (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a     general autoimmunity locus. Diabetes 2004; 53(11):3020-3. -   7. Nistico L, Buzzetti R, Pritchard L E, et al. The CTLA-4 gene     region of chromosome 2q33 is linked to, and associated with, type 1     diabetes. Belgian Diabetes Registry. Human molecular genetics 1996;     5(7):1075-80. -   8. Ueda H, Howson J M, Esposito L, et al. Association of the T-cell     regulatory gene CTLA4 with susceptibility to autoimmune disease.     Nature 2003; 423(6939):506-11. -   9. Vella A, Cooper J D, Lowe C E, et al. Localization of a type 1     diabetes locus in the IL2RA/CD25 region by use of tag     single-nucleotide polymorphisms. American journal of human genetics     2005; 76(5):773-9. -   10. Leiter E H, Lee C H. Mouse models and the genetics of diabetes:     is there evidence for genetic overlap between type 1 and type 2     diabetes? Diabetes 2005; 54 Suppl 2:S151-8. -   11. Gunderson K L, Steemers F J, Lee G, Mendoza L G, Chee M S. A     genome-wide scalable SNP genotyping assay using microarray     technology. Nature genetics 2005; 37(5):549-54. -   12. Fisher R A. Statistical Methods for Research Workers. 1958;     Hafner, New York, ed. 13. -   13. de Bakker P I, McVean G, Sabeti P C, et al. A high-resolution     HLA and SNP haplotype map for disease association studies in the     extended human MHC. Nature genetics 2006; 38(10):1166-72. -   14. Hirschhorn J N, Lohmueller K, Byrne E, Hirschhorn K. A     comprehensive review of genetic association studies. Genet Med 2002;     4(2):45-61. -   15. Finn R D, Mistry J, Schuster-Bockler B, et al. Pfam: clans, web     tools and services. Nucleic acids research 2006; 34(Database     issue):D247-51. -   16. Cambi A, Figdor C G. Levels of complexity in pathogen     recognition by C-type lectins. Current opinion in immunology 2005;     17(4):345-51.

While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. It will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the scope of the present invention, as set forth in the following claims. 

1. A method for detecting the presence or absence of at least one genetic alteration in a target nucleic acid isolated from a patient for the diagnosis of type 1 diabetes (T1D), said method comprising: a) providing a target nucleic acid from a patient sample, said target nucleic acid having a predetermined sequence in the normal population; b) assessing said target nucleic acid for the presence of a single nucleotide polymorphism which is indicative of an increased or decreased risk of developing T1D.
 2. The method as claimed in claim 1, wherein said genetic alteration is selected from the group consisting of inversion, deletion, duplication, and insertion of at least one nucleotide in said sequence.
 3. The method of claim 1, wherein said target nucleic acid is assessed for genetic alterations via a method selected from the group consisting of size analysis, hybridization of allele specific probes, labeled allele-specific primer extension, oligomer ligation, DNA sequencing, single-stranded conformation polymorphism, and quantitative PCR.
 4. The method as claimed in claim 1, wherein said genetic alteration is a single nucleotide polymorphism at the 12q13 region of chromosome 12, said SNP being associated with reduced risk of developing T1D.
 5. The method as claimed in claim 1, wherein said genetic alteration is a single nucleotide polymorphism at the 12813 region of chromosome 12, said SNP being associated with increased risk of developing T1D.
 6. The method of claim 5, wherein said SNP associated with T1D is present on a region of chromosome 12q13 harboring RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3 genes.
 7. The method of claim 5, wherein said SNP is present on locus 18 and comprises an allele selected from the group consisting of G of rs10876864, C of rs1701704 and G of rs773107.
 8. The method as claimed in claim 1, wherein said genetic alteration comprises at least one of the single nucleotide polymorphisms set forth in Tables 1-3.
 9. A method for determining the presence or absence of at least one specific nucleotide in a target nucleic acid for the diagnosis of T1D as claimed in claim 1, said method comprising the steps of: a) providing a detectable amount of a target nucleic acid polymer isolated from a chromosomal region known to be associated with diabetes, b) hybridizing said detectable amount of the nucleic acid polymer with one or more oligonucleotide primers, wherein each primer has a nucleotide sequence that is complementary to a sequence in the target nucleic acid polymer, c) exposing the hybridized nucleic acid polymer to a polymerization agent in a mixture containing at least one deoxynucleotide, said deoxynucleotide comprising a detectable label, d) analyzing the polymerization mixture of step (c) for the presence or absence of the primer extension product containing the labeled deoxynucleotide, whereby the identity of the specific nucleotide at the defined site is determined; and e) assessing said target nucleic acid for the presence of a genetic alteration at said at least one single nucleotide loci, the presence of the polymorphism being associated with an increased risk of developing T1D.
 10. A kit for practicing the method of claim
 9. 11. A nucleic acid comprising at least one SNP identified in Tables 1-3.
 12. A microarray comprising at least one nucleic acid of claim 11, said nucleic acid optionally being between 10 and 50 nucleotides in length. 13-22. (canceled)
 23. A single nucleotide polymorphism associated with an increased risk of developing T1D as claimed in claim 11 selected from the group consisting of an G of rs10876864, C of rs1701704 and G of rs773107 or a SNP in Table
 1. 24. A method for identifying agents which modulate autoimmune beta cell destruction leading to T1D comprising: a) providing cells expressing a SNP selected from the group consisting of an G of rs10876864, C of rs1701704 and G of rs773107; b) providing cells which express the cognate sequence lacking the SNPs of step a); c) contacting the cells of steps a) and b) with an agent; and d) determining whether said agent alters beta cell destruction of the cells of step a) relative to those of step b), thereby identifying agents which modulate autoimmune beta cell destruction.
 25. An siRNA composition comprising at least one nucleotide sequence selected from the group found in Tables 5-10 in a pharmaceutically acceptable carrier for delivery to a patient. 26-29. (canceled)
 30. A method for identifying a combination of siRNA molecules as claimed in claim 25 effective for down-regulating the expression of a protein selected from the group consisting of RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3, comprising: a) contacting a cell with an effective amount of at least two siRNA molecules; b) assessing the effect of said siRNAs on down regulation of RPS26 expression relative to untreated cells.
 31. The method of claim 30, wherein said cells are selected from the group consisting of INS cells, PC12 cells, MING cells, pancreatic beta islet cells and alpha TC6 cells.
 32. The method of claim 31 wherein modulatory effects of said siRNAs on a parameter selected from the group consisting of insulin secretion, glucagon secretion and glucosamine induced beta cell apoptosis is determined. 